the peroxisome proliferator - activated receptors ( ppars ) are ligand - inducible transcription factors that belong to the hormone nuclear receptor superfamily . they are involved in the transcriptional control of genes regulating various physiological processes such as lipid homeostasis , glucose metabolism , inflammation , cellular differentiation and proliferation [ 1 , 2 ] . ppars act mainly as lipid sensors , regulating metabolism in response to dietary lipid intake and direct the subsequent metabolism and storage of lipids . three isoforms have been identified , ppar , ppar/ , and ppar. these three isoforms differ in terms of their tissue distribution , ligand specificity and physiological role . ppar acts primarily to regulate energy homeostasis through its ability to stimulate the breakdown of fatty acids and cholesterol , driving gluconeogenesis and reduced triglyceride levels . this receptor in particular acts as a lipid sensor , binding fatty acids and initiating their subsequent metabolism . the ppar/ receptors bind and respond to vldl - derived fatty acids , eicosanoids , including prostaglandin a1 , and are involved in fatty acid oxidation . ppar operates in the metabolism of lipid and carbohydrate metabolism and its activation is related to reduction of glucose levels . peroxisome proliferator - activated receptors ( ppars ) are activated by small , lipophilic compounds and regulate gene expression by forming heterodimers with retinoid - x - receptors . once activated the ppar / retinoid - x - receptors heterodimer binds to the specific dna sequence [ peroxisome proliferator response element ( ppre ) ] on the promoter region of ppar target genes [ 2 , 5 ] to modulate transcriptional activity . the activity of ppars is also regulated by posttranslational modification such as phosphorylation and sumoylation [ 6 , 7 ] . thus , phosphorylation can negatively or positively affect ppar activity depending on which specific protein residue is modified [ 811 ] . alternatively , ppar sumoylation promotes the repression of inflammatory or adipocyte differentiation genes [ 6 , 13 ] . peroxisome proliferator - activated receptor alpha ( ppar ) ligands include fibrates that are commonly used for the treatment of hypertriglyceridemia and wy14,643 and gw7647 . ppar/ ligands include the prostacyclin pgi2 , and synthetic compounds gw0742 , gw501516 , and gw7842 . all ppars can be activated by polyunsaturated fatty acids with different affinities [ 14 , 15 ] . naturally occurring ppar ligands include long chain fatty acids , other natural lipid ligands , eicosanoids and the prostaglandin 15d - pgj2 , but also few nonsteroidal antiinflammatory drugs , as ibuprofen , fenoprofen , and indomethacin a [ 1517 ] . synthetic thiazolidinediones ( tzds ) , including pioglitazone and rosiglitazone were originally designed as ppar agonists and are currently in clinical use as insulin - sensitizing agents for the treatment of type 2 diabetes [ 15 , 18 ] . peroxisome proliferator - activated receptor alpha ( ppar ) is highly expressed in metabolically active tissues , such as liver , kidney , intestine , heart , skeletal muscle , adrenal gland and pancreas during foetal development of rodents [ 19 , 20 ] . in adult rodent organs , the distribution of ppar is similar to its foetal pattern of expression . in the central nervous system ( cns ) , ppar is expressed at very low levels predominantly in astrocytes and ppar is most highly expressed in tissues that catabolise fatty acids , such as the adult liver , heart , kidney , large intestine and skeletal muscle . ppar/ is the most abundant in the cns , ppar/ is expressed ubiquitously in virtually all tissues and earlier during foetal development . ppar/ mrna is present ubiquitously , with a higher expression in the digestive tract and placenta [ 1921 ] . in the cns ppar/ is preferentially found in the cerebellum , brain stem and cortex , was enriched in the dentate gyrus / ca1 region and was found in immature oligodendrocytes . given the role of ppar in regulating glucose and lipid metabolism , in promoting lipid storage and adipocyte differentiation [ 2426 ] , ppar is expressed in white and brown adipose tissue and in the cns during foetal development of rodents . ppar is abundantly expressed in white adipose tissue , and is present at lower levels in skeletal muscle , heart and liver [ 1921 ] . in the cns , ppar is expressed in several cell types including neurons , astrocytes , oligodendrocytes and microglia [ 16 , 2628 ] . in neurons , ppar immunoreactivity appears mainly as a nuclear labeling although sometimes cytoplasmic staining is detectable in some cortical neuron . high levels of ppar have been found in the piriform cortex and olfactory tubercle , in the basal ganglia , in rhomboid , centromedial , and parafascicular thalamic nuclei , in the reticular formation , and in the stellate cells of cerebellar cortex . parkinson s disease ( pd ) is a chronic neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons of the substantia nigra pars compacta , resulting in deficiency of nigrostriatal dopamine transmission . one pathological feature of the disease is the presence of lewy bodies that are intraneuronal proteinaceous cytoplasmic inclusions , which include -synuclein , ubiquitin , and neurofilaments , and are found in all affected brain regions . pd occurs most commonly as a sporadic form ( 95  % ) , while familial forms make up the remainder , involving mutations in an array of proteins that include pink1 , parkin , lrrk2 , fbxo-7 and dj-1 , although environmental factors such as chemicals , pesticides and metals may increase the risk of developing pd [ 3032 ] . currently there is no effective treatment that slows the progression of the disease , and management remains symptomatic . although the specific pathomechanism of pd is still unclear , there is ever growing evidence suggesting the involvement of mitochondrial dysfunction , oxidative stress , protein dysfunction , apoptosis , autophagy and chronic neuroinflammation . in recent years , the neuroprotective effects of ppar agonists has been assessed in several in vitro and in vivo models of several neurodegenerative conditions including pd [ 33 , 34 ] , alzheimer s disease [ 35 , 36 ] , cerebral ischemia   and amyotrophic lateral sclerosis . mitochondrial dysfunction , oxidative stress , proteosomal dysfunction , neuroinflammation , autophagy and apoptosis are all implicated in the pathogenesis of pd . environmental factors and toxins ( rotenone , mptp , mpp and 6-ohda ) directly induce both oxidative stress and mitochondrial dysfunction . different toxins increase oxidative stress ( ros ) and cause mitochondrial dysfunction , both increase [ ca ] , decrease atp , decrease mitochondrial membrane potential , decrease oxygen consumption and cause failure in autophagy , proteosomal dysfunction and abnormal protein aggregation which ultimately lead to neuronal death . dj-1 and parkin mutations cause aggregation of -synuclein and parkin / pink-1 mutations cause failure in autophagy . mutations in parkin also increase expression of the paris , thereby repressing the expression of pgc-1. ppar agonists inhibit microglial activation and reduce inflammation by decreasing expression of cytokines , tnf- , cox2 and inos . ppar agonists reduced apoptosis by inhibition of bax , il2 , il1 and by increasing bcl-2 expression . ppar agonists increase antioxidant defences , mitochondrial biogenesis , oxygen consumption , mitochondrial membrane potential , autophagy , pgc-1 and other transcription factors . moreover , pgc-1 induces the expression of downstream target genes involved in mitochondrial biogenesis , transcription factors and antioxidant defences . thus , pgc-1 and ppar agonists regulate the expression of several target genes involved in neuronal survival and neuroprotection by inhibiting mitochondrial dysfunction , oxidative stress , proteosomal dysfunction , autophagy , neuroinflammation and apoptosis pathways involved in neuroprotection by ppar and pgc-1 in pd . mitochondrial dysfunction , oxidative stress , proteosomal dysfunction , neuroinflammation , autophagy and apoptosis are all implicated in the pathogenesis of pd . environmental factors and toxins ( rotenone , mptp , mpp and 6-ohda ) directly induce both oxidative stress and mitochondrial dysfunction . different toxins increase oxidative stress ( ros ) and cause mitochondrial dysfunction , both increase [ ca ] , decrease atp , decrease mitochondrial membrane potential , decrease oxygen consumption and cause failure in autophagy , proteosomal dysfunction and abnormal protein aggregation which ultimately lead to neuronal death . dj-1 and parkin mutations cause aggregation of -synuclein and parkin / pink-1 mutations cause failure in autophagy . mutations in parkin also increase expression of the paris , thereby repressing the expression of pgc-1. ppar agonists inhibit microglial activation and reduce inflammation by decreasing expression of cytokines , tnf- , cox2 and inos . ppar agonists reduced apoptosis by inhibition of bax , il2 , il1 and by increasing bcl-2 expression . ppar agonists increase antioxidant defences , mitochondrial biogenesis , oxygen consumption , mitochondrial membrane potential , autophagy , pgc-1 and other transcription factors . moreover , pgc-1 induces the expression of downstream target genes involved in mitochondrial biogenesis , transcription factors and antioxidant defences . thus , pgc-1 and ppar agonists regulate the expression of several target genes involved in neuronal survival and neuroprotection by inhibiting mitochondrial dysfunction , oxidative stress , proteosomal dysfunction , autophagy , neuroinflammation and apoptosis 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin ( mptp ) administration has been widely used in animals to selectively target dopaminergic neurons and so reproduce pd symptoms . in the acute mptp model  in the rodent , however , pioglitazone treatment did not alleviate mptp - induced loss of tyrosine hydroxylase in the striatum and had only partially protective effects on the mptp - induced decline in striatal tissue levels of dopamine . in another study pioglitazone was shown to protect against chronic mptp - induced neurotoxicity , with reduced activation of microglia , reduced induction of inos - positive cells and fewer glial fibrillary acidic protein ( gfap ) positive cells in both striatum and substantia nigra . recently it has also been shown that pioglitazone protected against mptp induced neurotoxicity by the inhibition of monoamine oxidase - b in the striatum . therefore , blocking the conversion of mptp to its active toxic metabolite mpp , via inhibition of monoamine oxidase - b . treatment with rosiglitazone in the chronic mptp ( plus probenecid ) mouse model , completely prevented motor and olfactory dysfunction and loss of dopaminergic neurons in the substantia nigra . rosiglitazone partially protected against loss of striatal dopamine , whereas decreases in dopac and dynorphin mrna in the striatum were completely abolished . also astrogliosis and number of activated microglia were reduced as assessed by gfap and cd11b immunostaining , respectively , without affecting mptp metabolism . in the same model of mptp plus probenecid , treatment with rosiglitazone was also effective in protecting against partial degeneration of the substantia nigra and the decline of striatal dopamine . in a recent study , pioglitazone was also neuroprotective and antiinflammatory in an mptp model in the rhesus monkey , with a significant improvement in a clinical rating score . behavioral recovery was associated with preservation of nigrostriatal dopaminergic markers and reduced infiltration by cd68-positive macrophages in the nigrostriatal area . more recently , the administration of a non - tzd partial ppar agonist , was again shown to be neuroprotective in mptp - induced neurodegeneration , associated with downregulation of neuroinflammation , decreased oxidative stress , and modulation of ppar and ppar coativator-1 ( pgc-1 ) expression . intrastriatal injection of lipopolysaccharide ( lps ) in rats has also served to model degeneration of dopaminergic neurons in pd . in this model pioglitazone prevented the loss of dopaminergic neurons and the decline in striatal dopamine levels . pioglitazone normalized cox-2 expression and increased the expression of uncoupling protein 2 ( uncoupling protein 2 is one of five acknowledged uncoupling proteins and it is located in the inner mitochondrial membrane , where it helps reduce the proton gradient . also , uncoupling protein 2 may be involved in pd ) and increased the expression of mitoneet , while inos induction and oxidative stress were reduced [ 46 , 47 ] . in dopaminergic neuron - glial cultures , pioglitazone protected neurons from lps by inhibiting abnormal microglial activation , interfering with phosphorylation of jun n - terminal kinase and nuclear factor kappa - b , and by suppressing cyclooxygenase-2 expression and the subsequent prostaglandin e(2 ) synthesis . pioglitazone also protected dopaminergic neurons against lps damage by inhibiting inos expression and nitric oxide generation by differential regulation of p38 mitogen - activated protein kinase and the phosphoinositide 3-kinase / protein kinase b pathway . microglial activation has been implicated in the pathogenesis of pd and is believed to aggravate neuronal injury [ 33 , 50 ] . the anti - inflammatory actions of rosiglitazone against lps were mediated by its ability to increase il-4 expression . thus , production of pro - inflammatory cytokines has been described in a 6-hydroxydopamine ( 6-ohda ) model of pd , where microglial activation was observed . a recent study demonstrated that pioglitazone did not exert any protection in the 6-ohda model . the lack of effect of pioglitazone in this model was attributed to the severity of the damage caused by 6-ohda . however , pioglitazone protected against neuronal loss and motor behaviour in the acute mptp model . in the 6-ohda - lesioned rat , the activation of ppar receptors by rosiglitazone significantly attenuated the production of both cox-2 and tnf- expression and increased gfap expression in the striatum . ppar activation increased mitochondrial membrane potential and protected cells from apoptosis following growth factor withdrawal . pioglitazone also increased neuronal glucose uptake and restored brain atp levels [ 56 , 57 ] . pioglitazone increased mitochondrial dna content , oxygen consumption , pgc-1 and mitochondrial transcription factor a ( tfam ) in human adipose tissue and in the neuronal - nt2 cell line [ 5861 ] . in addition , pioglitazone stabilizes mitoneet , an iron - sulfur containing outer mitochondrial membrane protein which regulates oxidative capacity [ 6365 ] . rotenone is a complex i inhibitor and has been widely used to model pd [ 39 , 66 ] . consequently , pioglitazone protected against the reduction of locomotor activity and decline in striatal dopamine levels induced by rotenone . in a recent study , it was found that rotenone irreversibly decreased mitochondrial mass , membrane potential and oxygen consumption , while increasing free radical generation and autophagy in human differentiated sh - sy5y cells . similar changes were seen in pink1 knockdown cells , in which the membrane potential , oxygen consumption and mitochondrial mass were all decreased . in both models , all these changes were reversed by treatment with rosiglitazone , which increased mitochondrial biogenesis , increased oxygen consumption and suppressed free radical generation and autophagy . rosiglitazone significantly increased the expression of proteins related with antioxidant defences and mitochondrial biogenesis ( sod1 , nuclear factor ( erythroid - derived 2)-like 2 ( nrf2 ) , nad(p)h : quinone oxidoreductase 1 ( nqo1 ) , pgc-1 and tfam ) . thus , rosiglitazone was neuroprotective in two different models of mitochondrial dysfunction associated with pd through a direct impact on mitochondrial function . nrf2 is normally sequestered in the cytoplasm by its inhibitor keap1 . in response to oxidative stress , nrf2 translocates to the nucleus and dimerizes with another member of the capncollar / basic leucine zipper family of transcription factors , activating transcription by binding to an antioxidant response element ( are ) located in the promoter of a number of antioxidant genes , including nqo1 , heme oxygenase-1 ( ho-1 ) and glutathione s - transferase [ 70 , 71 ] . a number of studies have suggested that nrf2 and nqo1 protect against cellular dysfunction in different models of pd [ 7274 ] . recently , it  was demonstrated that rosiglitazone increased expression of nrf2 and the antioxidant enzyme ho-1 acting through the ppar-pathway , enhancing elimination of ros in hepatocytes . the protective effects of tzds have been attributed also to their antioxidant and anti - apoptotic properties . for that reason , rosiglitazone was shown to protect human neuroblastoma cells against mpp induced mitochondrial dysfunction by anti - oxidant properties and anti - apoptotic activity via inducing expression of sod and catalase and regulating the expression of bcl-2 and bax and increase the mitochondrial membrane potential . in the mpp model , rosiglitazone treatment did not alter sod activity but there was an increase of glutathione s - transferase activity and the protective effects of rosiglitazone were not blocked by the ppar antagonist gw9662 , suggesting that these effects may be independent of ppar activation . acetaldehyde , an inhibitor of mitochondrial function , causes neuronal death by inducing generation of intracellular reactive oxygen species and cellular apoptosis in human neuroblastoma cells . rosiglitazone reversed acetaldehyde induced apoptosis by inducing the expression of anti - oxidant enzymes such as sod and catalase and by regulating expression of bcl-2 and bax . ppar coactivator-1 ( pgc-1 ) was discovered in brown adipose tissue as a ppar coactivator during the thermogenic response to cold . pgc-1 can regulate other nuclear receptors such as the thyroid hormone receptor , the oestrogen receptor , and the oestrogen - related receptor  , aside of acting as a coactivator for ppars . on the other hand , pgc-1 acts also as a coactivator for other transcription factors such as the nuclear respiratory factors 1 and 2 ( nrf-1 and 2 ) , tfam , myocyte enhancer factor 2 , foxo receptors and hepatic nuclear factor 4 . pgc-1 is highly expressed in tissues with a high - energy demand , such as brown adipose tissue , brain , heart , liver , pancreas , skeletal muscle and kidney . it plays a central role in driving and coordinating mitochondrial biogenesis and respiration , gluconeogenesis and glucose transport , glycogenolysis , fatty acid oxidation , peroxisomal remodeling , muscle fiber - type switching , oxidative phosphorylation and is preferentially expressed in muscle enriched for type i myocytes and can convert the type ii myocytes to type i fibers . in addition , pgc-1 also regulates the expression of several ros detoxifying enzymes , such as sod1 and 2 , catalase and glutathione peroxidase-1 . the activity of pgc-1 is influenced by post - transcriptional modifications , such as protein phosphorylation , acetylation , sumoylation , and methylation [ 81 , 85 , 86 ] . pgc-1 expression can be induced by cold exposure , fasting , and exercise , which require energy expenditure [ 79 , 83 , 87 ] . it has been reported that pgc-1 expression is decreased with aging , possibly owing to decreased sirtuin1 ( sirt1 ) levels   or by the action of p53 that is activated by telomere shortening and suppresses pgc-1 . drugs such as resveratrol , can act by decreasing pgc-1 acetylation , producing a subsequent increase in pgc-1 activity and its downstream genes . the role pgc-1 , which is involved in mitochondrial biogenesis and respiration , has been implicated in pd . as mentioned above , pgc-1 induces the expression of ros scavenging enzymes ( glutathione peroxidase-1 , catalase and sod ) and reduces oxidative stress . an increased vulnerability to mptp induced degeneration of nigral dopaminergic neurons was observed in pgc-1 knockout mice , suggesting a critical role of pgc-1 in neuroprotection . therefore , increasing pgc-1 levels dramatically protected neural cells from oxidative stress and cell death . these studies suggested compelling evidence for a role of pgc-1 in neurodegenerative diseases and as a good candidate for the treatment of pd . the mechanisms of neuroprotection by pgc-1 in pd are shown in ( fig .  1 ) . activation of pgc-1 increased the expression of nuclear - encoded subunits of the mitochondrial respiratory chain and prevented the dopaminergic neuron loss induced by mutant -synuclein or the pesticide rotenone in cellular disease models . also , it has been shown that pgc-1 knockdown increased -synuclein accumulation and led to down regulation of the akt / gsk-3 signaling pathway in human neuronal cells . a substrate for parkin , the parkin - interacting substrate ( paris ) , is a zinc - finger protein which is highly expressed in the substantia nigra . paris represses the expression of pgc-1 and nrf-1 and the site of interaction between paris and pgc-1 is a sequence that is involved in the regulation of insulin responsiveness and energy metabolism . conditional knockout of parkin in adult animals led to progressive loss of dopamine neurons which was dependent on paris expression . moreover , overexpression of paris led to the selective loss of dopamine neurons in the substantia nigra , and this was reversed by either parkin or pgc-1 coexpression . a recent study reported that pink1 mutations impair parkin recruitment to mitochondria in neurons , increased mitochondrial copy number , and upregulation of pgc-1 . other studies , have shown that transgenic overexpression of pgc-1 or activation of pgc-1 by resveratrol protect dopaminergic neurons in the mptp mouse model of pd . recently it  was shown that adenoviral delivery of pgc-1 in the nigrostriatal system increased dopaminergic death . this effect could be the result of excessive overexpression of pgc-1 , resulting in mitochondrial hyperactivity and increased production of ros . apparently , the studies related to the role of pgc-1 in pd have provided inconsistent data regarding the effects of pgc-1 activation or overexpression in pd . in conclusion , a number of molecular pathways including oxidative stress , mitochondrial dysfunction , protein dysfunction , apoptosis , autophagy and neuroinflammation are implicated in the pathophysiology of pd . as currently available drugs can not slow down the progression of the disease , using a combination of several pharmacological agents may offer better promise for neuroprotection , modulating several molecular pathways involved in the pathophysiology simultaneously . ppar agonists and pgc-1 exhibit a wide range of activities that positively influence the pathology of pd in experimental models , and they have the capacity to be neuroprotective by regulating the expression of genes involved in neuronal survival processes . the compelling results from in vitro and in vivo models of pd underline the beneficial effects of ppar agonists and pgc-1 for future therapies . thus , ppar agonists and pgc-1 could be valuable potential therapeutic targets for neurodegenerative diseases . finally , understanding the molecular mechanisms by which ppar and pgc-1 exert their neuroprotective effects will be helpful in developing an effective treatment for pd .
the peroxisome proliferator - activated receptor gamma ( ppar ) is a ligand - activated transcriptional factor that belongs to the nuclear hormone receptor superfamily . 
 ppar was initially identified through its role in the regulation of glucose and lipid metabolism and cell differentiation . 
 it also influences the expression or activity of a number of genes in a variety of signalling networks . 
 these include regulation of redox balance , fatty acid oxidation , immune responses and mitochondrial function . 
 recent studies suggest that the ppar agonists may serve as good candidates for the treatment of several neurodegenerative disorders including parkinson s disease ( pd ) , alzheimer s disease , huntington s disease and amyotrophic lateral sclerosis , even though multiple etiological factors contribute to the development of these disorders . 
 recent reports have also signposted a role for ppar coactivator-1 ( pgc-1 ) in several neurodegenerative disorders including pd . in this review , 
 we explore the current knowledge of mechanisms underlying the beneficial effects of ppar agonists and pgc-1 in models of pd .