Title of Invention: Compounds and compositions for treating tissue ischemia Abstract: There is disclosed a genus of compounds and pharmaceutical compositions that are protective for mitigating damage associated with tissue ischemia, particularly stroke (CNS ischemia), and ischemia of the myocardium. The present invention further provides a method for treating tissue damage caused by ischemia. Lastly, the present invention provides a method for treating tissue damage caused by providing a compound that inhibits the cytotoxic activity of 3-aminopropanal. Brief Summary: The present invention provides a genus of compounds and pharmaceutical compositions that are protective for mitigating damage associated with tissue ischemia, particularly stroke (CNS ischemia), and ischemia of the myocardium. The present invention further provides a method for treating or preventing tissue damage precipitated by injury, disease or insult, particularly the tissue damage caused by ischemia. Lastly, the present invention provides a method for treating or preventing tissue damage by providing compounds that and compositions that inhibit or neutralize the cytotoxic activity of 3-aminopropanal. Cerebral ischemia, a leading cause of disability and mortality world-wide, is mediated by a cascade of molecular cytotoxins that kill potentially viable cells in the brain. The polyamines, spemine, spermidine, and putrescine, which are among the most abundant molecules in mammalian brain, have been implicated in the pathogenesis of ischemic brain damage (Zhang et al., Proc. Natl. Acad. Sci. USA 91:10883-10887, 1994; Harman and Shaw, Br. J. Pharmac. 73:165-174, 1981; Bergeron et al., J. Med. Chem. 39:5257-5266, 1996; Glantz et al., J. Basic. Clin. Physiol. Pharmacol. 7:1-10, 1996; Dempsey et al., Neurosurg. 17:635-640, 1985; and Schmitz et al., Neurosurg. 33:882-888, 1993). Polyamine biosynthesis is increased following the onset of cerebral ischemia, due to an ischemia-mediated induction of ornithine decarboxylase, a key synthetic enzyme in the polyamine biosynthetic pathway. Spermine was linked to development of glutamate-mediated cytotoxicity, because it can bind to the NR1 subunit of the NMDA receptor and potentiate glutamate-mediated cell damage (Traynelis et al., Science 268:873-876, 1995; Traynelis and Cull-Candy. J. Physiol. (Lond.) 433:727-763, 1991; and Sullivan et al., Neuron 13:929-936, 1994). Administration of experimental therapeutics which inhibit ornithine decarboxylase limit the development of ischemic brain damage in experimental animal models of stroke [ref]. Thus, the accumulation of polyamines in the ischemic brain occupies an important role in the pathogenesis of stroke (Kindy et al., J. Cereb. Blood Flow Metab. 14:1040-1045, 1994). Brain spermine and spermidine levels are actually decreased by cerebral ischemia (Paschen, J. Neurochem. 49:35-37, 1987; and Paschen, Cerebrovasc. Brain Metab. Rev. 4:59-88, 1992). This observed decline of tissue spermine and spermidine levels is accompanied by an increase in brain levels of putrescine (Paschen, Mol. Chem. Neuropathol. 16:241-271, 1992; Paschen, Cerebrovasc. Brain Metab. Rev. 4:59-88, 1992; Morgan, Bachrach and Heimer, eds. CRC Publications, 203-229, 1989; and Paschen et al., Acta Neuropathol. 76:388-394, 1988). Further, intracerebral putrescine levels correlated significantly with the volume of brain cell death. Putrescine does not interact with the NMDA receptor, and does not potentiate its cytotoxic activity. A possible explanation for these results may reside in the catabolism of polyamines via the xe2x80x9cinterconversion pathwayxe2x80x9d which is dependent upon the activity of tissue polyamine oxidase (Seiler and Bolkenius, Neurochem. Res. 10:529-544, 1985; Seiler et al., Med. Biol. 59:334-346, 1981; Bolkenius and Seiler, Int. J. Dev. Neurosci. 4:217-224, 1986; and Bolkenius et al., Biochim. Biophys. Acta 838:69-76, 1985). This ubiquitous enzyme, which is present in high levels in brain and other mammalian tissues, cleaves spermine and spermidine via oxidative deamination to generate the end products putrescine and 3-aminopropanal (Seiler and Bolkenius, Neurochem. Res. 10:529-544, 1985; Seiler, In Yu et al., eds. Elsevier Science, 333-344, 1995; Morgan, Essays in Biochemistry 23:82-115, 1987; and Houen et al., Acta Chem. Scand. 48:52-60, 1994). 3-Aminopropanal is known for its cytotoxicity to primary endothelial cells, fibroblasts, and a variety of transformed mammalian cell lines (Bouzyk and Rosiek, Cancer Lett. 39:93-99, 1988; Brunton et al., Toxic. in Vitro 8:337-341, 1994; Gaugas and Dewey, Br. J. Cancer 39:548-557, 1978; Morgan et al., J. Biochem. 236:97-101, 1986; and Ferrante et al., J. Immunol. 133:2157-2162, 1984). 3-Aminopropanal has also been implicated as a mediator of programmed cell death in murine embryonic limb buds, and may contribute to the development of necrosis in some tumors (Parchment and Pierce, Cancer Res 49:6680-6686, 1989; and Kurihara et al., Neurosurg. 32:372-375, 1993). Inhibition of polyamine oxidase with aminoguanidine blocked generation of 3-aminopropanal in cell cultures following the addition of spermine, and prevented subsequent cytotoxicity (Ferrante et al., J. Immunol. 133:2157-2162, 1984; Morgan, Essays in Biochemistry 23:82-115, 1987; and Parchment and Pierce, Cancer Res. 49:6680-6686, 1989). On a molar basis, the LD50 concentration of 3-aminopropanal to cells is similar to the cytotoxicity of glutamate. In contrast, putrescine is not cytotoxic to cells, even in the millimolar range, but its rate of production through polyamine oxidation correlates directly with the formation of a directly cytotoxic aldehyde, 3-aminopropanal. In addition, in the data first being reported herein in glial cells, 3-aminopropanal mediates apoptosis by activation of an interleukin-1 beta converting enzyme (ICE)-dependent signaling pathway, whereas in neurons it causes necrotic cell death. Cerebral ischemia (stroke) is a debilitating condition resulting from a sudden cessation of blood flow to an area of the brain, resulting in a loss of brain tissue. There are no available therapies to reverse the neurological deficits caused by neuronal death in the infarct zone. Stroke is a major public health problem in the United States wherein about 550,000 strokes occur each year. Cerebral ischemia afflicts individuals of all age groups, but the incidence doubles with each decade over 45 and reaches 1-2% per year in the population of individuals over 75 years of age. If a patient survives, major disability can result with loss of ability to communicate, ambulate, see, coordinate and/or reason. Standard therapy is often ineffective at preventing brain infarction and is meant to support cardiovascular and respiratory function, control intracranial pressure, and prevent recurrent stroke. There is also a class of protease enzymes that are designed to dissolve blood clots, only for those strokes caused by blood clots potentially useful in brain ischemia but (as opposed to bleeding) and these agents only function to restore some blood flow in limited situations. During the evolution of cerebral infarction (stroke), a core of densely ischemic tissue becomes rapidly and irreversibly damaged. Cellular damage in the surrounding area, termed the xe2x80x9cischemic penumbra,xe2x80x9d progresses more slowly. Following an ischemic insult, the process of tissue destruction may not be completed for hours or even days (Kirino et al., Acta Neuropathol. 64:139-147, 1984; and Petito et al. Neurology 37:1281-1286, 1987). There is a temporary window of opportunity for an intervention to prevent ischemic tissue from progressing to infarction. In humans, this window is thought to extend from about 2-4 hours following the onset of ischemia, after which time the efficacy decreases rapidly (Ginsberg and Pulsinelli, Ann. Neurol. 36:553-554, 1994). During the therapeutic window, the target for therapeutic neuroprotection is the ischemic penumbra, a volume of brain tissue around the ischaemic core, which receives reduced blood flow and contains compromised, but potentially viable tissue. Studies have identified important cytotoxic mediators that cause cell death in the early hours after the onset of ischemia. A number of molecular substrates of normal brain, as well as extrinsic factors delivered by the circulation, contribute to the development of cell cytotoxicity during ischemia. These include, but are not limited to, glutamate, aspartate, nitric oxide, calcium, free radicals, zinc, cytokines, arachidonic acid metabolites, and advanced glycation end products (AGEs). Advanced glycation endproducts are a group of protein modifying adducts that were implicated in the pathogenesis of diabetic complications. AGEs were found to be cerebrotoxic in the ischemic penumbra (Zimmerman et al., Proc. Natl. Acad. Sci. USA 92:3744-3748, 1995). In addition, aminoguanidine, a small molecule inhibitor of AGE cross-linking reactions, effectively abrogated the cerebrotoxicity of AGEs during focal cerebral ischemia (Zimmerman et al., Proc. Natl. Acad. Sci. USA 92:3744-3748, 1995). Aminoguanidine was also found to be cerebroprotective during focal ischemia in normal, non-diabetic animals, independent of exogenous AGEs (Zimmerman et al., Surg. Forum. 45:600-603, 1994). Aminoguanidine further provided cerebroprotection in a model of focal stroke when administered within 2 hours after the onset of focal cerebral ischemia (Cockroft et al., Stroke 27:1393-1398, 1996). It was considered that the mechanism of action was inhibition of polyamine oxidase (PAO), an enzyme that produces toxic, reactive aldehyde metabolites by oxidation of biogenic amines. The cascade of cytotoxicity that is initiated by reduced blood flow is followed by a drop in ATP levels and a reduction of oxidative phosphorylation. As a result, membrane potentials fall, leading to release of K+ and an excessive amount of glutamate and other excitatory amino acids (EAAs) in a process called excitotoxicity. This will, in turn, over-activate N-methyl-D-aspartate (NMDA), amino-3-hydroxy-5-methyl-4-isoxasole-4-propionate (AMPA), kainate (KA), and 1S,3R-trans-1-amino-cyclopentyl-1,3dicarboxylate (trans-ACPD) receptors (Faroquil and Horrocks, Brain Res. 16:171-191, 1991). Elevated glutamate leads to excessive Ca2+ influx, primarily by excitatory amino acid receptor channel activation, as well as swelling and osmotic lysis as a result of depolorization mediated influx of Na+, Clxe2x88x92 and water (Faroquil and Horrocks, Brain Res. 16:171-191, 1991). This elevation of intracellular Ca2+ activates phospholipases, lipases, proteases and protein kinases, leading to eventual breakdown of phospholipid membranes, cytoskeletal alterations, arachidonic acid release, and potentiation of the free radical cascade (Manfred et al., Biochem. Pharm. 50:1-16, 1995). Other modulators of NMDA receptors include Zn2+, histamine, certain neuroactive steroids, arachidonic acid, polyamines and protons or pH (Collinridge and Lester, Pharmacol. Rev. 74:143-210, 1989; and McBain and Mayer, Physiol. Rev. 74:723-760, 1994). Moreover, an NMDA receptor antagonist, MK-801, can exert a neuroprotective effect in animal models of cerebral ischemia (Olney et al., J. Neurosci. 9:1701-1704, 1989). Ischemia also leads to formation of reactive oxygen species (ROS), activation of lipid peroxidation, and a reduction in the endogenous antioxidants ascorbate, glutathione, ubiquinone and xcex1-tocopherol in brain tissue. The mitochondrial respiratory chain and reaction sequences catalyzed by cyclooxygenase and lipoxygenase are important production sites for superoxide anion (O2xe2x88x92), hydrogen peroxide (H2O2) and hydroxy radical (OHxe2x88x92). Activated oxygen species are also formed during autooxidation of catecholamines and in the xanthine reaction. Nitric oxide (NO) is another mediator of tissue injury in cerebral ischemia. NO concentrations increase acutely in the brain after middle cerebral artery (MCA) occlusion, from approximately 10 nM to 2.2 xcexcM by a porphyrinc microsensor assay (Beckman et al., Proc. Natl. Acad. Sci. USA 87:1620, 1990). In addition to these other suspected mediators of ischemic tissue damage, 3-aminopropanol is an enzymatic by-product of the oxidative cleavage of the polyamines spermine and spermidine by PAO in mammalian cells (Holtta, Biochemistry 16:91-100, 1997). The cytotoxicity resulting from co-incubation of PAO activity with spermine and spermidine has been abolished by aminoguanidine (Gabl et al., Chemicobiological Interactins 22:91-98, 1978; and Henle et al., Cancer Res. 46:175-182, 1986). 3-Aminopropanal has also been implicated in causing programmed cell death in murine embryonic limits buds (Parchment et al., Cancer Res. Arch. 49:6680-6686, 1989) and in necrosis of solid tumors. These data provides a need in the art to find inhibitors of PAO activity that are likely to have therapeutic utility in treating tissue ischemia, particularly mitigating damage to the ischemic penumbra experienced in stroke, but also in non-neuronal tissue such as muscle tissue (e.g., smooth muscle and cardiac muscle). The present invention provides a stroke-damage mitigating compound having a formula I: wherein R and R1 are independently hydrogen, sulfamide, carboxyamide, cyano, straight or branched C1-6 alkyl, straight or branched C2-6 alkenyl, straight or branched C1-6 alkoxy, a straight chain C1-6 alkyl or a straight chain C2-6 alkenyl having an ether link or an ester link, toluenyl, COOH, nitrate, or halide (Br, Cl, I, F), wherein both R and R1 cannot be hydrogen, wherein R2 and R3 are independently hydrogen, sulfamide, carboxyamide, cyano, straight or branched C1-6 alkyl, straight or branched C2-6 alkenyl, straight or branched C1-6 alkoxy, a straight chain C1-6 alkyl or a straight chain C2-6 alkenyl having an ether link or an ester link, toluenyl, COOH, nitrate, or halide (Br, Cl, I, F). Preferably, R and R1 are meta to each other and to the heteroatom. Preferably, R is COOH. Preferably, R1 is COOH. Preferably, R2 and R3 are both hydrogen. Most preferably, R and R1 are each COOH, and R2 and R3 are both hydrogen. Preferred compounds of formula I include, for example, 1-phenacyl-2,3-dicarboxypyridinium bromide; 1-phenacyl-2,4-dicarboxypyridinium bromide; 1-phenacyl-2,5-dicarboxypyridinium bromide; 1-phenacyl-2,6-dicarboxypyridinium bromide; 1-phenacyl-2,3-dicarboxyimidepyridinium bromide; 1-phenacyl-2,4-dicarboxyimidepyridinium bromide; 1-phenacyl-2,5-dicarboxyimidepyridinium bromide; and 1-phenacyl-2,6-dicarboxyimidepyridinium bromide; 1-phenacyl-2,3-dicarboxyimidepyrdinium bromide; 1-phenacyl-2,4-dicarboxyimidepyrdinium bromide; 1-phenacyl-2,5-dicarboxyimidepyrdinium bromide; and 1-phenacyl-2,6-dicarboxyimidepyrdinium bromide. The present invention provides a pharmaceutical composition comprising a compound from formula I in a pharmaceutically acceptable carrier, wherein formula I comprises: wherein R and R1 are independently hydrogen, sulfamide, carboxyamide, cyano, straight or branched C1-6 alkyl, straight or branched C2-6 alkenyl, straight or branched C1-6 alkoxy, a straight chain C1-6 alkyl or a straight chain C2-6 alkenyl having an ether link or an ester link, toluenyl, COOH, nitrate, or halide (Br, Cl, I, F), wherein both R and R1 cannot be hydrogen, wherein R2 and R3 are independently hydrogen, sulfamide, carboxyamide, cyano, straight or branched C1-6 alkyl, straight or branched C2-6 alkenyl, straight or branched C1-6 alkoxy, a straight chain C1-6 alkyl or a straight chain C2-6 alkenyl having an ether link or an ester link, toluenyl, COOH, nitrate, or halide (Br, Cl, I, F). Preferably, R and R1 are meta to each other and to the heteroatom. Preferably, R is COOH. Preferably, R1 is COOH. Preferably, R2 and R3 are both hydrogen. Most preferably, R and R1 are each COOH, R2 and R3 are both hydrogen. The present invention further provides a method for treating tissue ischemia to mitigate ischemic damage, comprising administering an effective amount of a compound of formula I, wherein formula I comprises: wherein R and R1 are independently hydrogen, sulfamide, carboxyamide, cyano, straight or branched C1-6 alkyl, straight or branched C2-6 alkenyl, straight or branched C1-6 alkoxy, a straight chain C1-6 alkyl or a straight chain C2-6 alkenyl having an ether link or an ester link, toluenyl, COOH, nitrate, or halide (Br, Cl, I, F), wherein both R and R1 cannot be hydrogen, wherein R2 and R3 are independently hydrogen, sulfamide, carboxyamide, cyano, straight or branched C1-6 alkyl, straight or branched C2-6 alkenyl, straight or branched C1-6 alkoxy, a straight chain C1-6 alkyl or a straight chain C2-6 alkenyl having an ether link or an ester link, toluenyl, COOH, nitrate, or halide (Br, Cl, I, F). Preferably, R and R1 are meta to each other and to the heteroatom. Preferably, R is COOH. Preferably, R1 is COOH. Preferably, R2 and R3 are both hydrogen. Most preferably, R and R1 are each COOH, and R2 and R3 are both hydrogen. The invention further provides a method for treating tissue ischemia to mitigate ischemic damage, comprising administering an effective amount of a compound of formula II, wherein formula II comprises: wherein R1 and R2 are independently selected from the group consisting of hydrogen, hydroxy C1-6 alkyl, C1-6 alkoxy C1-6 alkyl, and R1 and R2 together with their ring carbons may be an aromatic fused ring; wherein Z is hydrogen or an amino group; wherein Y is hydrogen or a group of the formula xe2x80x94CH2COR; wherein R is C1-6 alkyl, C1-6 alkoxy, hydroxy, amino, aryl, or xe2x80x94CH2R3 wherein R3 is H, C1-6 alkyl, C2-6 alkenyl, or C4-6 aryl. Preferably, the compound of formula II is a halide (Cl, Br, F or I), tosylate, methanesulfonate or mesitylene sulfonate salt. The present invention further provides a method for inhibiting tissue damage, comprising administering an effective amount of a compound that inhibits or neutralizes the cytotoxic activity of 3-aminopropanal. Preferably, the diseases resulting from tissue ischemia are myocardial infarction or stroke. Detailed Description: The present invention arose out of a series of experiments wherein cerebral damage subsequent to induced focal ischemia was found to be mediated by the induction of brain polyamine oxidase activity. Moreover, the cytotoxic end product 3-aminopropanal accumulated in the ischemic brain at levels that are lethal to neurons and glial cells. These data further demonstrated that inhibition of polyamine oxidase activity with structurally distinct pharmaceutical compounds prevented the formation of 3-aminopropanal, and provided significant protection against the development of cerebral damage following permanent cerebral artery occlusion in rats. Finally, data is presented that certain compounds with the potential to react with 3-aminopropanal are efficacious in limiting the extent of tissue damage following ischemia 3-Aminopropanal. Four closely related lines of evidence support the role of 3-aminopropanal as a cytotoxic mediator of cellular and tissue damage in cerebral ischemia. First, cerebral ischemia mediates an early induction of polyamine oxidase activity. Second, the cytotoxic enzyme product 3-aminopropanal accumulates during the early response to cerebral ischemia (FIG. 2), but is not a produced in normally perfused controls. Third, 3-aminopropanal production in the ischemic brain increases prior to the onset of significant cellular degeneration, with tissue 3-aminopropanal levels rising further during the period of progressive cell death. Fourth, 3-aminopropanal is a potent cytotoxin which activates apoptosis via an ICE-dependent mechanism in glial cells, and necrosis in neurons. Considered together, these data offer an explanation for the correlation between brain levels of putrescine, a stable end product of terminal polyamine oxidation, and infarct volume (Dempsey et al., Neurosurg. 17:635-640, 1985; Traynelis et al., J. Physiol. (London) 433:727-763, 1991; Gilad et al., Mol. Chem. Neuropathol. 18:197-210, 1993), since catabolism of spermine and spermidine by polyamine oxidase produces both a stable, non-toxic end product (putrescine) and a potent cytotoxin (3-aminopropanal). The latter product mediates cell death, and the former accumulates in correlation to the extent of damage. Previous observations suggest that polyamines can prevent apoptosis in neuronal cultures (Harada and Sugimoto, Brain Res 753:251-259, 1997; and Xie et al., Exp. Cell Res 230:386-392, 1997), or amplify glutamate-mediated cell cytotoxicity (Pegg et al., Biochem. Soc. Trans. 22:846-852, 1994). Cell survival in the ischemic zone is likely to be critically dependent upon the balance between the direct effects of polyamines, and the cytotoxic effects of their metabolite, 3-aminopropanal. There has been some controversy as to whether both 3-aminopropanal and 3-acetamidopropanal can produce acrolein in vivo, a known mediator of cytotoxicity and apoptosis (Li et al., Toxicol. Appl. Pharmacol. 145:331-339, 1997; and Fernandez et al., Br. J. Cancer 72:1194-1199, 1995). Thus, it is likely that several products of polyamine oxidation could further augment the cytotoxicity of 3-aminopropanal. When considered together and without being bound by theory, these observations add further credence to the hypothesis that enhanced polyamine oxidation during ischemia is deleterious. Without being bound by theory, these data suggest the following mechanism of brain cell death during cerebral ischemia: dead and dying cells in the densely hypoxic core release stores of intracellular spermine and spermidine, which is catabolized by polyamine oxidase. The resultant production of 3-aminopropanal causes apoptosis in surrounding glial cells, and necrosis of neurons, which in turn release more spermine and spermidine as substrate for polyamine oxidase. This cytotoxic mechanism spreads to involve a larger volume of potentially viable cells surrounding the ischemic core. It is likely that in concert with the excitatory amino acids, activated oxygen species, nitric oxide, TNF, IL-1, IL-6, and platelet-activating factor (Meistrell III et al., SHOCK 8:341-348, 1997; Zhang et al., Stroke 27:317-323, 1996; Coyle and Puttfarcken, Science 262:689-695,193; Rothwell and Strijbos, Int J Dev. Neurosci 13:179-185, 1995; Irikura et al., Proc. Natl. Acad. Sci. USA 92:6823-6827, 1995; Rothwell and Relton, Cerebrovasc Brain Metab Rev 5:178-198, 1993;Taupin et al., J Neuroimmunol. 42:177-185, 1993; Saito et al., Neurosci Lett 206:149-152, 1996; Choi, J Neurobiol 23:1261-1276, 1992; and Montague et al., Science 263:973-76, 1994), 3-aminopropanal is positioned as a proximal mediator in the cytoxicity cascade of cerebral ischemia Previous observations have noted that inhibition of ICE (IL-1xcex2 converting enzyme) protects against the development of apoptosis during cerebral ischemia (Friedlander et al., J. Exp. Med. 185:933-940, 1997; Gillardon etal., Brain Res. Mol. Brain Res. 50:16-22, 1997; and Hara et al., J. Cereb. Blood Flow Metab. 17:370-375, 1997). Since the stimulus to apoptosis during cerebral ischemia is unknown, it is reasonable to suggest a proximal role for 3-aminopropanal. Further, it was previously reported that TNF synthesis is upregulated during the first 12 hours of brain ischemia, which cytokine participates in the subsequent development of brain damage (Meistrell III et al., SHOCK 8:341-348, 1997). Spermine is a direct inhibitor of TNF synthesis in human peripheral blood mononuclear cells (Zhang et al., J. Exp. Med. 185:1-10, 1997). Moreover, the role of decreasing spermine levels during cerebral ischemia is unexplained and not reported. Centrally administered 3-aminopropanal directly stimulated intracerebral TNF synthesis (data not illustrated in examples). These data provide additional evidence for a proximal role of 3-aminopropanal in the pathogenesis of stroke. Early production and potent cytotoxicity of 3-aminopropanal define a proximal role of this aldehyde in the ischemic mediator cascade. Thus, polyamine oxidation contributes to cell cytotoxicity and these data do not contradict the potential role of other cytotoxic factors. Polyamines and polyamine oxidase are ubiquitous in all mammalian tissues (Seiler, Biochimica et Biophysica Acta. 615:480-488, 1980). Table 1 provides a time course study of cell viability after exposure to 3-aminopropanal. Glial or neuronal cells were exposed to an LD100 concentration of 3-aminopropanal (750 xcexcM) for the times indicated, followed by replacing the media with fresh OPTI-MEM (medium) for a total incubation time of 20 hr. Cell viability was determined by MIT assay (data shown are meanxc2x1s.e). These data support the notion that polyamine oxidase-derived 3-aminopropanal is a mediator of the brain damaging sequelae of cerebral ischemia, which can be therapeutically modulated. Brain polyamine oxidase activity was increased significantly within two hours after the onset of ischemia in brain homogenates (15.8xc2x10.9 nmol/h/mg protein) as compared to homogenates prepared from the normally perfused contralateral side (7.4xc2x10.5 nmol/h/mg protein) (P less than 0.05). The major catabolic products of polyamine oxidase are putrescine and 3-aminopropanal. Although 3-aminopropanal is a potent cytotoxin, essential information was previously lacking on whether 3-aminopropanal is produced during cerebral ischemia. 3-aminopropanal accumulated in the ischemic brain within 2 hours after permanent forebrain ischermia in rats, but not in normally perfused brain. Cytotoxic levels of 3-aminopropanal (750 xcexcM) were achieved prior to the onset of significant cerebral cell damage, and increased in a time-dependent manner. Elevated 3-aminopropanal levels occurred in association with the development of progressive neuronal and glial cell death. Glial cell cultures that were exposed to 3-aminopropanal underwent apoptosis (L.D.50=275 xcexcM) whereas neurons were killed by necrotic mechanisms (L.D.50=90 xcexcM). The tetrapeptide ICE inhibitor (Ac-YVAD-CMK) prevented 3-aminopropanal-mediated apoptosis in glial cells. Finally, treatment of rats with two structurally distinct inhibitors of polyamine oxidase (aminoguanidine and chloroquine) attenuated brain polyamine oxidase activity, prevented the production of 3-aminopropanal, and significantly protected against the development of ischemic brain damage in vivo. Considered together, these results indicate that polyamine oxidase-derived 3-aminopropanal is a mediator of the brain damaging sequelae of cerebral ischemia, which can be therapeutically modulated. Synthesis, Compounds and Formulations The compounds of Formula I may have an asymmetric carbon atom which may occur in the R, R1 and R3 side-chains; optical isomers may likewise occur in the R, R1 and R3 side-chains of the compounds of Formula II. The isomers of a racemic mixture of any of these compounds can be separated by methods known to those skilled in the art and the isomeric preparations thus purified and isolated can be tested, by methods known to those skilled in the art or taught herein, to determine if such an isomeric preparation (as opposed to the corresponding racemic mixture) is more desirable, e.g., has less toxicity or greater potency, for use in the methods of this invention. The compounds, compositions and treatment methods of this invention can be used to prevent or inhibit tissue necrosis and cell death in a variety of settings, particularly as the circumstances may be understood to involve the evolution of 3-aminopropanal and its role as a cytotoxin that propagates cellular damage. Such additional indications have in common the need to inhibit xe2x80x9cinnocent bystanderxe2x80x9d cell death. In other words, the compounds, compositions and methods of this invention find particular utility in preventing the spread of cell death outward from a fatally damaged, non-viable core into a potentially viable surrounding or penumbral zone. The initiating damage at the core may be due to any of a variety of causes (e.g., ischemia, embolism, thrombosis, hypoperfusion, injury, trauma, disease, heat, cold, chemical exposure, surgery, exposure to endogenous, environmental or therapeutic cytotoxins, radiation, necrosis, apoptosis, etc.); the compounds, compositions and methods of this invention will then find utility in preventing or limiting cellular damage and cell death in tissue adjacent to the non-viable core. Without accepting any limitation implied by mechanistic explanation, the compounds, compositions and methods of this invention are thought to operate in such diverse settings by molecular interference with and neutralization of the cytotoxic activity of 3-aminopropanal, which cytotoxin arises naturally from metabolism of polyamines released in the core and in the penumbra as cellular damage propagates outward from the initiating site. In each such instance, the compounds, compositions and methods of this invention may be usefully employed to limit tissue damage ancillary or adjacent to the site of initiating damage. Compounds of formula I can be synthesized according to the following procedure. A general procedure for the synthesis of N-Phenyacyl Pyridinum Bromide derivatives: A solution of Pyridine (1.58 g, 20.0 mmol) and Bromoacetophenone (4.00 g, 20.0 mmol) in 50 ml of ethanol was refluxed for 6 h. The reaction progress was monitored by TLC using a mixture of ethyl acetate:methanol:water (4:2:1 and 1.0% of ammonia) as developing solvent. Upon cooling the reaction mixture, the product came out of solution as white precipitate which was filtered and recrystallized from ethanol as white needle crystal (MP. 216.4-220xc2x0 C.) in 97% yield. Further characterizations of the new products were carried out using NMR and mass spectrometer. Compounds according to formula 2 have been described, for example, in U.S. Pat. No. 5,656,261, the disclosure of which is incorporated by reference herein. Such compounds include, for example, 3-amino-thiazolium mesitylenesulfonate; 2,3-diamino-thiazolium mesitylenesulfonate; 3-(2-methoxy-2-oxoethyl)-4,5-dimethylthiazolium bromide; 3-(2-methoxy-2-oxoethyl)-4-methylthiazolium bromide; 3-(2-phenyl-2-oxoethyl)-4-methylthiazolium bromide; 3-(2-phenyl-2-oxoethyl)-4,5-dimethylthiazolium bromide; 3-amino4-methyl-thiazolium mesitylene sulfonate; 3-(2-methoxy-2-oxoethyl)-5-methyl-thiazolium bromide; 3-(2-phenyl-2-oxoethyl)-5-methyl-thiazolium bromide; 3-(2-[41-bromophenyl]-2-oxoethyl)-thiazolium bromide; 3-(2-[41-bromophenyl]-2-oxoethyl)-4-methyl-thiazolium bromide; 3-(2-[41-bromophenyl]-2-oxoethyl)-5-methyl-thiazolium bromide; 3-(2-[41-bromophenyl]-2-oxoethyl) -4,5-dimethylthiazolium bromide; 3-(2-methoxy-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl)-thiazolium bromide; 3-(2-phenyl-2-oxoethyl)-4methyl-5-(2-hydroxyethyl)-thiazolium bromide; 3-(2-[41-bromophenyl]-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl) thiazolium bromide; 3,4-dimethyl-5-(2-hydroxyethyl)-thiazolium iodide; 3-ethyl-5-(2-hydroxyethyl)-4-methyl thiazolium bromide; 3-benzyl-5-(2-hydroxyethyl))-4-methyl-thiazolium chloride; 3-(2-methoxy-2-oxoethyl)-benzothiazolium bromide; 3-(2-phenyl-2-oxoethyl)-benzothiazolium bromide; 3-(2-[41-bromophenyl)-2-oxoethyl)-benzo-thiazolium bromide; 3-(carboxymethyl)-benzothiazolium bromide; 2,3-diamino-benzothiazolium mesitylenesulfonate; 3-(2-amino-2-oxoethyl)-thiazolium bromide; 3-(2-amino-2-oxoethyl)-4-methyl-thiazolium bromide; 3-(2-amino-2-oxoethyl)-5-methyl-thiazolium bromide; 3-(2-amino-2-oxoethyl)-4,5-dimethyl-thiazolium bromide; 3-(2-amino-2-oxoethyl)-benzothiazolium bromide; 3-(2-amino-2-oxoethyl)-4-methyl-5-(2-hydroxyethyl) thiazolium bromide; 3-amino-5-(2-hydroxyethyl)-4-methyl-thiazolium mesitylenesulfonate; 3-(2-methyl-2-oxoethyl) thiazolium chloride; 3-amino-4-methyl-5-(2-acetoxyethyl) thiazolium mesitylenesulfonate; 3-(2-phenyl-2-oxoethyl) thiazolium bromide; 3-(2-methoxy-2-oxoethyl)-4-methyl-5-(2-acetoxyethyl) thiazolium bromide; 3-(2-amino-2-oxoethyl)-4-methyl-5-(2-acetoxyethyl) thiazolium bromide; 2-amino-3-(2-methoxy-2-oxoethyl) thiazolium bromide; 2-amino-3-(2-methoxy-2-oxoethyl) benzothiazolium bromide; 2-amino-3-(2-amino-2-oxoethyl) thiazolium bromide; 2-amino-3-(2-amino-2-oxoethyl) benzothiazolium bromide; 3-[2-(4xe2x80x2-methoxyphenyl)-2-oxoethyl]-thiazolinium bromide; 3-[2-(2xe2x80x2,4xe2x80x2-dimethoxyphenyl)-2-oxoethyl]-thiaxolinium bromide; 3-[2-(4xe2x80x2-fluorophenyl-2-oxoethyl]-thiazolinium bromide; 3-[2-(2xe2x80x2,4xe2x80x2-difluorophenyl)-2-oxoethyl]-thiazolinium bromide; 3-[2-(4xe2x80x2-diethylaminophenyl)-2-oxoethyl]-thiazolinium bromide; 3-propargyl-thiazolium bromide; 3-propargyl-4-methyl thiazolium bromide; 3-propargyl-5-methyl thiazolium bromide; 3-propargyl-4, 5-dimethyl thiazolium bromide; 3-propargyl-4-methyl-5-(2-hydroxyethyl)-thiazolium bromide; 3-(2-[3xe2x80x2-methoxyphenyl]-2-oxoethyl)-thiazolium bromide; 3-(2-[3xe2x80x2-methoxy phenyl]-2-oxoethyl)-4methyl-5-(2xe2x80x2-hydroxyethyl)-thiazolium bromide; 3-(2-[3xe2x80x2-methoxyphenyl]-2-oxoethyl-benzothiazolium bromide; 2,3-diamino-4-chlorobenzothiazolium mesitylenesulfonate; 2,3-diamino-4-methyl-thiazolium mesitylene sulfonate; 3-amino-4-methyl-5-vinyl-thiazolium mesitylene sulfonate; 2,3-diamino-6-chlorobenzothiazolium mesitylenesulfonate; 2,6-diamino-benzothiazole dihydrochloride; 2,6-diamino-3 [2-(4xe2x80x2-methoxyphenyl)-2-oxoethyl]benzothiazolium bromide; 2,6-diamino-3 [2-(3xe2x80x2-methoxyphenyl)-2-oxoethyl]benzothiazolium bromide; 2,6-diamino-3 [2-(4xe2x80x2-diethylaminophenyl)-2-oxoethyl]benzothiazolium bromide; 2,6-diamino-3 [2-(4xe2x80x2-bromophenyl)-2-oxoethyl]benzothiazolium bromide; 2,6-diamino-3 (2-(2-phenyl-2-oxoethyl) benzothiazolium bromide; 2,6-diamino-3 [2-(4xe2x80x2-fluorophenyl-2-oxoethyl]benzothiazolium bromide; 3-acetamido-4-methyl-5-thiazolyl-ethyl acetate mesitylenesulfonate; 2,3-diamino-5-methylthiazolium mesitylenesulfonate; 3-[2-(2xe2x80x2-naphthyl)-2-oxoethyl]-4-methyl-5-(2xe2x80x2-hydroxyethyl)-thiazolium bromide; 3-[2-(3xe2x80x2,5xe2x80x2-Di-tert-butyl-4xe2x80x2-hydroxyphenyl)-2-oxoethyl[-4-methyl-5-(2xe2x80x2-hydroxyethyl)-thiazolium bromide; 3-[2-(2xe2x80x2,6xe2x80x2-Dichlorophenethylamino)-2-oxoethyl]-4-methyl-5-(2xe2x80x2-hydroxyethyl)-thiazolium-bromide; 3xe2x80x2[2-Dibutylamino-2-oxoethyl]-4-methyl-5-(2xe2x80x2-hydroxyethyl)-thiazolium bromide; 3-[2-4xe2x80x2-carbethoxyanilino)-2-oxoethyl]-4-methyl-5-(2xe2x80x2-hydroxyethyl)-thiazolium bromide; 3-[2-(2xe2x80x2,6xe2x80x2-Diisopropylanilino)-2-oxoethyl]-4-methyl-5-(2xe2x80x2-hydroxyethyl)-thiazolium bromide; 3-amino-4-methyl-5-[2(2xe2x80x2,6xe2x80x2-dichlorobenzyloxy) ethyl]-thioazolium mesitylenesulfonate; 3-[2-(4xe2x80x2-carbmethoxy-3xe2x80x2-hydroxyanilino)-2-oxoethyl]-4-methyl-5-(2xe2x80x2-hydroxyethyl)-thiazolium bromide; 2,3-Diamino-4,5-dimethyl thiazolium mesitylene sulfonate; 2,3-Diamino-4-methyl-5-hydroxyethyl-thiazolium mesitylene sulfonate; 2,3-Diamino-5-(3xe2x80x2,4xe2x80x2-trimethylenedioxy phenyl) thiazolium mesitylene sulfonate; 3[2-(1xe2x80x2,4xe2x80x2-benzodioxan-6-yl)-2-oxoethyl]-4-methyl-5-(2xe2x80x2-hydroxyethyl-thiazolium bromide; 3xe2x80x2[2-(3xe2x80x2,4xe2x80x2-trimethylenedioxyphenyl)-2-oxoethyl]-4-methyl-5-(2-hydroxyethyl)-thiazolium bromide; 3-(2-[1xe2x80x2,4-benzodioxan-6-yl]-2-oxoethyl)-thiazolium bromide; 3-[2-(3xe2x80x2,4xe2x80x2-trimethylenedioxyphenyl)-2-oxoethyl]-thiazolium bromide; 3-[2-(3xe2x80x2,5xe2x80x2-di-tert-butyl-4xe2x80x2-hydroxyphenyl)-2-oxoethyl]-thiazoliun bromide; 3-[2-(3xe2x80x2,5xe2x80x2-di-tert-butyl-4xe2x80x2-hydroxyphenyl)-2-oxoethyl]-4-methyl-thiazolium bromide; 3-[2-(3xe2x80x2,5xe2x80x2-di-tert-butyl-4xe2x80x2-hydroxyphenyl)-2-oxoethyl]-5-methyl-thiazolium bromide; 3-[2-(3xe2x80x2,5xe2x80x2-di-tert-butyl-4xe2x80x2-hydroxyphenyl)-2-oxoethyl]-4,5-dimethyl-thiazolium bromide; 3-[2-(3xe2x80x2,5xe2x80x2-di-tert-butyl-4xe2x80x2-hydroxyphenyl)-2-oxoethyl-[benzothiazolium bromide; 1-methyl-3-[2-(3xe2x80x2,5xe2x80x2-di-tert-butyl-4xe2x80x2-hydroxyphenyl)-2-oxoethyl]-imidazolium bromide; 3-[2-(4xe2x80x2-n-pentylphenyl)-2-oxoethyl]-thiazolinium bromide; 3-[2-(4xe2x80x2-n-pentylphenyl)-2-oxoethyl]-4-methyl-5-(2xe2x80x2-hydroxyethyl)-thiazolinium bromide; 3-[2-4xe2x80x2-diethylaminophenyl)-2-oxoethyl]-4-methyl-5-(2xe2x80x2-hydroxyethyl)-thiazolinium bromide; 3-(2-phenyl-2-oxoethyl)-4-methyl-5-vinyl-thiazolium bromide; 3-[2-(3xe2x80x2,5xe2x80x2-tert-butyl-4xe2x80x2-hydroxyphenyl)-2-oxoethyl)-4-methyl-5-vinyl-thiazolium bromide; 3-(2-tert-butyl-2-oxoethyl) -thiazolium bromide; 3-(2-tert-butyl-2-oxoethyl)-4-methyl-5-(2xe2x80x2-hydroxyethyl)-thiazolium bromide; 3-(3xe2x80x2-methoxybenzyl)-4-methyl-5-(2xe2x80x2-hydroxyethyl)-thiazolium chloride; 3-(2xe2x80x2,6xe2x80x2-dichlorobenzyl)-4-methyl-5-(2xe2x80x2-hydroxyethyl)-thiazolium chloride; 3-(2xe2x80x2-nitrobenzyl)-4-methyl-5-(2xe2x80x2-hydroxyethyl)-thiazolium bromide; 3 [2-(4xe2x80x2-chlorophenyl)-2-oxoethyl]-thiazolium bromide; 3 [2-(4xe2x80x2-chlorophenyl)-2-oxoethyl]-4-methyl-5-(2xe2x80x2-hydroxyethyl)-thiazolium bromide; and 3 [2-(4xe2x80x2-methoxyphenyl)-2-oxoethyl]-4-methyl-5-(2xe2x80x2-hydroxyethyl)-thiazolium bromide. Therapeutic Uses, Routes of Administration and Formulations The present invention provides novel compounds, pharmaceutical formulations and methods of treatment to mitigate ischemic damage. Effective doses of the therapy, as described below, may be formulated in suitable pharmacological carriers and may be administered by any appropriate means, including, but not limited to injection (intravenous, intraperitoneal, intramuscular, intracranial, intramyocardial, subcutaneous), by absorption through epithelial or mucocutaneous linings (oral mucosa, rectal and vaginal epithelial linings, nasopharyngeal mucosa, intestinal mucosa); orally, transdermally or any other means available within the pharmaceutical arts. A compound can be administered to a human patient by itself or in pharmaceutical compositions where it is mixed with suitable carriers or excipients at doses to treat or mitigate tissue ischemia or to mitigate ischemic damage. Preferably, the organ sites of treatment are the CNS and the myocardium. A therapeutically effective dose further refers to that amount of the compound sufficient to treat or mitigate tissue ischemia or to mitigate ischemic damage. Therapeutically effective doses may be administered alone or as adjunctive therapy in combination with other treatments for tissue ischemia or to mitigate tissue ischemic damage. Techniques for the formulation and administration of the compounds of the instant application may be found in xe2x80x9cRemington""s Pharmaceutical Sciencesxe2x80x9d Mack Publishing Co., Easton, Pa., latest addition. Suitable routes of administration may, for example, include oral, rectal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intracranial, intrascerebroventricular, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections, and optionally in a depot or sustained release formulation. Furthermore, one may administer the agent of the present invention in a targeted drug delivery system, for example in a liposome coated with a tissue-targeting antibody. The liposomes will be targeted to and taken up selectively by target tissue cells. The pharmaceutical compositions may be manufactured by means of conventional mixing, dissolving, dragee-making, levitating, emulsifying, encapsulating, entrapping, or lyophilizing processes. Pharmaceutical compositions for use in accordance with the invention may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. For injection, the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers, such as Hank""s solution, Ringer""s solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are usually known in the art. For oral administration, the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers. Such carriers enable the compounds to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner. For administration by inhalation, the compounds for use according to the invention are delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, such as, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. The compounds may be formulated for parenteral administration by injection, such as, by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulary agents such as suspending, stabilizing and/or dispersing agents. Pharmaceutical formulations for parenteral administration include, for instance, aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle before injection, such as, sterile pyrogen-free water. Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various of sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for stabilization may be employed. The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. Many of the compounds described herein and identified as useful for treating or mitigating tissue ischemia or mitigating ischemic damage may be provided as salts with pharmaceutically compatible counterions. Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc.; or bases. Salts tend to be more soluble in aqueous or other protonic solvents that are the corresponding free base forms. Examples of pharmaceutically acceptable salts, carriers or excipients are well known to those skilled in the art and can be found, for example, in Remington""s Pharmaceutical Sciences, 18th Edition, A. R. Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1990. Such salts include, but are not limited to, sodium, potassium, lithium, calcium, magnesium, iron, zinc, hydrochloride, hydrobromide, hydroiodide, acetate, citrate, tartrate, malate salts, and the like. Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve their intended purpose. More specifically, a therapeutically effective amount means an amount effective to prevent development of or to alleviate the existing symptoms of the subject being treated. Determination of the effective amounts is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein. For any compound used in the method of the invention, the therapeutically effective dose can be estimated initially from cell culture assays. In addition, therapeutically useful doses from in vivo experiments are provided with the in vivo data of preferred embodiments illustrated herein. Such information can be used to more accurately determine useful doses in humans. A therapeutically effective dose refers to that amount of the compound that results in a reduction in the otherwise expected severity of stroke of damage in a prolongation of survival in a patient. Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical, pharmacological, and toxicological procedures in cell cultures or experimental animals for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50. Compounds which exhibit high therapeutic indices are preferred. The data obtained from cell culture assays or animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the desired modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data; such as, the concentration necessary to achieve a 50-90% inhibition of polyamine-derived or 3-aminopropanal-mediated cellular damage (in vitro) or achieve a reduction in the otherwise expected severity of stroke or ischemic damage in vivo using the assays described herein. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays, bioassays or immunoassays can be used to determine plasma concentrations. The amount of composition administered will be dependent on the subject being treated, on the subjects weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician. Screening Assays The present invention further provides an in vivo screening assay comprising administering a polyamine compound or 3-aminopropanal into the brain parenchyma of a test animal by microinjection, administering a test compound or control agent locally or systemicly, and measuring cortical cytotoxicity in stained brain sections from the test animals generated by the location of microinjection. Preferably, the polyamine compound is spermine or spermidine or metabolites thereof. Preferably, the test animal is a rat. Preferably, cytotoxicity of stained brain sections is measured by planimetric analysis. Example 2 below provides an experiment using this in vivo assay procedure and demonstrates cytotoxic activity of 3-aminopropanal, spermine and spermidine but not putrescine. The model was verified by systemic administration of polyamine oxidase inhibitors chloroquine and aminoguanidine. The present invention further provides an in vitro screening assay comprising exposing cultured glial cells or neuronal cells related cell lines to 3-aminopropanal at a concentration of from about 50 to about 1000 xcexcM, adding various concentrations of test compound or control media to the cell cultures, incubated under cell culture conditions for a period of from about 5 minutes to about 20 hours, and determining the percentage of cell viability. Preferably, the concentration of 3-aminopropanal in the cell culture medium is approximately 80 xcexcM. Preferably, the method for determining cell viability is by measuring metabolically-dependent reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT). Another method for determining cell death is by looking for evidence of apoptosis, for examply by a terminal doxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) method (Gavrieli et al., J. Cell. Bio. 119:493-501, 1992). Example 3 below provides additional working details for the in vitro screening assay, and Example 5 below shows exemplary assay results with a variety of test compounds. 3-Aminopropanal Mediates Tissue Damage Resulting from Ischemia Polyamine Oxidase Activity is Increased Following Ischemia To determine the role of polyamine oxidase activity and the metabolites it generates from polyamines in the tissue damage attendant to ischemia, an animal model of stroke was conducted. Lewis rats were subjected to focal cerebral ischemia by microsurgical occlusion of the middle cerebral artery in a standardized model as described previously (Zimmerman et al., Proc. Natl. Acad. Sci. USA 92:3744-3748, 1995; Cockroft et al., Stroke 27:1393-1398, 1996; and Meistrell III et al., SHOCK 8:341-348, 1997). Briefly, the ipsilateral common carotid artery was ligated and divided, the middle cerebral artery coagulated and divided distal to the lenticulostriate branch, and the contralateral common carotid temporarily occluded for 1 hr. The onset of ischemia in these experiments was defined as the time the middle cerebral artery was cut. For measurement of infarct volume, the animals were euthanized at the time indicated and fresh brain sections prepared (1 mm), immersed in 2,3,5-triphenyltetrazolium chloride (TTC) in 154 mM NaCl for 30 min at 37xc2x0 C., and total cerebral infarct volume measured by computerized quantitative planimetry as described elsewhere (Zimmerman et al., Proc. Natl. Acad Sci. USA 92:3744-3748, 1995; Cockroft et al., Stroke 27:1393-1398, 1996; and Bederson et al., Experientia 41:1209-1211, 1986). Similar measurements of stroke volume (infarct size) were obtained in separate experiments using planimetric analysis of brain sections stained with hematoxylin and eosin. All procedures involving animals in this example and in the following examples were conducted in conformity with institutional guidelines and under the approval of the Animal Care and Use Comminee of North Shore University Hospital-New York University Medical School. To measure tissue polyamine oxidase activity, brain homogenates were prepared from the anatomic region perfused by the middle cerebral artery, and total polyamine oxidase activity determined using a method described previously (Seiler and Bolkenius, Neurochem. Res. 10:529-544, 1985; Seiler et al., Med. Biol. 59:334-346, 198 1; and Milani et al., J. Neurosci. Res. 28:434-441, 1991), relying on the metabolic conversion of added spermine. Briefly, two hours after permanent occlusion of the middle cerebral artery, a 4 mm thick coronal section of the ipsilateral hemisphere encompassing the zone of ischemia (beginning 3 mm caudal from the frontal pole) was manually homogenized on ice in 1.5 ml of Hanks media containing 1 mM phenylmethylsulfonyl fluoride (PMSF) and centrifuged at 43,000xc3x97g for 30 min. Brain polyamine oxidase activity in the resultant homogenate supernatant was determined by addition of spermine at time zero (50 xcexcl of a 1 mM stock solution added per 1 ml of homogenate supernatant). For experiments using enzyme inhibitors, aminoguanidine or chloroquine in the pharmacological concentration range (50 xcexcM-5 mM) was added 5 minutes prior to spermine. The spermine-containing supernatants were maintained at 37xc2x0 C., and at time points up to 60 min after the addition of spermine, duplicate 200 xcexcl samples were removed and enzyme activity was stopped by addition of 10 xcexcl of 60% perchloric acid (PCA). Samples for HPLC analysis to detect spermine were prepared with dansyl chloride (200 xcexcl of 10 mg/ml dansyl chloride solution in acetone and 200 xcexcl saturated aqueous Na2CO3 per 50 xcexcl sample homogenate supernatant; 10 min incubation at 65xc2x0 C.; brief centrifugation to clear) and dansylated spermine was detected by fluoresence after fractionation by HPLC (20 xcexcl injectate; Vydac analytical C4 column eluted in a linear gradient from 0-100% methanol (in H2O) over 35 min). Enzyme activity was corrected for the protein content of the homogenate supernatants, and data expressed as meanxc2x1s.d.; n=3 brain homogenates per condition. Polyamine oxidase activity was significantly higher in homogenates prepared from ischemic hemispheres as compared to the contralateral (control) hemispheres (PAO activity after ischemia=15.8xc2x10.9/h/mg protein vs. PAO activity in contralateral controls=7.4xc2x10.5 nmol/h/mg protein, P less than 0.05; see FIG. 1). This increase in brain polyamine oxidase activity was detected as early as 2 hours after the onset of cerebral ischemia, suggesting that enhanced PAO activity occurred as part of the earliest response to ischemia Two known, structurally distinct inhibitors of polyamine oxidase activity, aminoguanidine and chloroquine (Seiler et al., Med. Biol. 59:334-346, 1981; Holtta, Biochem. 16:91-100, 1977; Flayeh, Clin. Chem. 34:401403, 1988; and Gahl and Pitot, Biochem. J. 202:603-611, 1982), were selected to determine the specificity of this spermine-metabolizing activity. Addition of either of these agents to homogenates of ischemic brain dose-dependently inhibited polyamine oxidase activity (see FIG. 1); chloroquine I.C.50=40 xcexcM; aminoguanidine I.C.50=400 xcexcM. These data indicate that within 2 hours after the onset of cerebral ischemia there is a specific induction of brain polyamine oxidase activity, and that this activity is susceptible to inhibition by known inhibitors of polyamine oxidase. 3-Aminopropanal Levels are Increased Following Ischemia To determine whether the increase in brain PAO activity associated with focal cerebral ischemia causes enhanced 3-aminopropanal production, a method to detect 3-aminopropanal in tissue samples was developed. To develop the method, 3-aminopropanal was prepared by hydrolysis of the diethyl acetal and then derivatized using 2,4-dinitrophenylhydrazine. Specifically, 3-aminopropanal was prepared by hydrolysis of 145 mM 3-aminopropanal diethyl acetal (TCI America) in 1.5 M HCl for 5 hours at room temperature. The reaction mixture was applied to a column (3 cmxc3x976 cm) of Dowex-50 (H+-form) ion exchange resin and eluted with a step gradient of 0-3 M HCl (160 ml; flow rate 0.7 ml/min). Fractions containing aldehyde, as determined by the method of Bachrach and Reches (Bachrach and Reches, Anal. Biochem. 17:38-48, 1966), were concentrated in a centrifugal evaporator at room temperature. The concentration of aldehyde (i.e., 3-aminopropanal) was determined spectrophotometrically at 531 nm, based on a reaction of aldehydes with 4-amino-3-hydrazino-5-mercapto-1,2,4-triazole (xe2x80x98Purpaldxe2x80x99; Aldrich) (Dickinson and Jacobsen, Chemical Communications 1719-720, 1970) with reference to a standard curve using propionaldehyde (Sigma). Acidic solutions of the aldehyde were neutralized with NaOH to physiological pH immediately before use. Vehicle control solutions were prepared, consisting of the same stoichiometric amounts of HCl and NaOH. To derivatize 3-aminopropanal, 2,4-dinitrophenylhydrazine (2,4-DNPH; 0.5 g of 2,4-DNPH dissolved in 11 ml of concentrated HCl/ethanol (1:10, v/v)) was refluxed for 10 seconds with aqueous 3-aminopropanal. The resulting 3-aminopropionaldehyde-2,4-dinitrophenylhydrazone derivative (3-AP-2,4-DNPH) was precipitated at room temperature, and collected by filtration. 1H-NMR spectrometry (DMSO-d6 and CDCl3, 270 MHz) of purified 2,4-dinitrophenylhydrazone derivative was employed to confirm its structure. The NMR spectrum revealed the presence of syn and anti isomers (1:1) with reynoldsjohn@example.org and xcex411.35. A standard curve was generated by an HPLC assay of the dansylated derivative of the compound (see below). An additional standard curve was constructed to quantify recovery of derivatized 3-aminopropanal from tissue homogenates. Briefly, a 4 mm thick brain slice obtained from the region perfused by the middle cerebral artery was homogenized manually, followed by addition of 3-aminopropanal (at 100, 150, 200, 300, 1000 nmol/ml) and 1.5 ml of 2,4-DNPH reagent. The samples were refluxed in the presence of the 2,4-DNPH reagent for 10 seconds, then 20 xcexcl of 60% perchloric acid (PCA) was added to stop the reaction, followed by 200 xcexcl of water. The samples were vigorously vortexed, centrifuged at 14,000 rpm for 30 min, and the supernatant concentrated to near dryness in a centrifugal evaporator. Samples were redissolved in 100 xcexcl of water, centrifuged for 10 min at 14,000 rpm to clear precipitates, then prepared for assay by HPLC. An HPLC detection system was used for detection of the derivatization products of 3-aminopropanal and 2,4-dinitrophenylhydrazine as follows. A Hewlett-Packard Model 1090 liquid chromatograph (Wilmington, Del., USA) equipped with an autosampler, photo diode-array and fluorescence detectors, and Chemstation operating software was used for all analyses. Detection by fluorescence was used, based on the reaction of 5-dimethyl-aminonapthalene sulfonyl-chloride (Dansyl chloride; Molecular Probes; relative fluorescence at 340 nm with excitation at 430 nm) with primary and secondary amines. Dansylation was performed by reacting 50 xcexcl of the sample with 200 xcexcl of 10 mg/ml dansyl chloride solution in acetone, 200 xcexcl of saturated Na2CO3 solution, 3 xcexcl 60% PCA and 3 xcexcl mM 1,7-diaminoheptane (Sigma), followed by incubation at 65xc2x0 C. for 10 min. 20 xcexcl of the resulting derivatized sample was injected onto a Vydac C-4 250xc3x974.6 mm column with 5 mm particle size. Using a flow rate of 1.0 ml/min, runs were initiated at 100% A (dH2O) and a linear gradient to 100% B (methanol) was performed over 45 min., followed by 5 min. of 100% B and a return to 100% A over 5 min. HPLC analysis of the 2,4-DNPH-derivatized, dansylated products revealed two peaks (24 min and 27 min) in equal ratio, attributable to the geometric isomers shown below (without dansylation): Electrospray ionization mass spectroscopy (EIMS) of the HPLC-purified products conformed to the expected mass ion, m/z 251, for the non-dansylated isomers. Brain homogenates were prepared as above after 2 hours or 25 hours of ischemia from rats subjected to Permanent focal cerebral ischemia, and the homogenates were derivatized with 2,4-dinitrophenylhydrazine as above. HPLC analysis of the dansylated derivatized homogenates revealed the appearance of two peaks, and EIMS confirmed their identities as the isomeric 3-aminopropanal-2,4-dinitrophenylhydrazine reaction products. The 3-aminopropanal derivatization products were not detected by this HPLC-based assay in brain homogenates prepared from sham-operated, normally perfused control animals, indicating that ischemia mediated the appearance of 3-aminopropanal. Thus, use of the quantitative HPLC-based assay for derivatized 3-AP (described above), which can reproducibly detect 1-2 xcexcM 3-aminopropanal in brain tissue, confirmed that 3-aminopropanal is not present or produced in homogenates prepared from normally perfused brain. However, within 2 hours after the onset of cerebral ischemia, it was observed that there were significantly increased 3-aminopropanal levels, which increased
{'bibliographic_information': "{'document_kind': 'B1', 'document_number': '06391899', 'document_date': '20020521', 'publishing_country_or_organization': 'US', 'title_of_invention': 'Compounds and compositions for treating tissue ischemia'}", 'source_file': './grant/2002/pg020521.XML', 'source_data': 'USPTO-Grant'}