INTRODUCTION:

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors, belonging to the nuclear receptor family.¹ There are three PPAR isotypes which include PPARα, PPARβ/δ and PPARγ. These are structurally homologous and display different physiological functions.²Activated PPARs are capable of transcriptional repression through DNA-independent protein-protein interactions with other transcription factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB).³PPARs are present mainly in the kidney, liver, small intestine, heart, brain etc.⁴In numerous chronic diseases such as, diabetes, cancer, inflammation and atherosclerosis the role of PPARs is well established.

PPARs are also expressed in the cardiovascular (endothelial cells, vascular smooth muscle cells, and monocytes/macrophages) system and its ligands have shown a role in different cardiovascular risk factor.^5,6,7Expression of PPARS in the brain cells like neurons and glia, suggested their role in in neuroprotection and neurodegenerative disorders.^8,9,10

Structure and Signaling Mechanism of PPAR:

PPARs possess 4 domains. N-terminal A/B domain contains a weak ligand-independent transactivation function called activation function 1 (AF-1). The DNA binding domain (DBD) contains two zinc-fingers that is the particularity of the nuclear receptor (NR) family. Through hinge region, the DBD is connected to the ligand binding domain (LBD). LBD possess a ligand dependent transactivation function activation function 2(AF-2). The LBD comprises a fold made by 12α helices and 4β sheets which forms a large hydrophobic pocket for ligands to bind. LBD serves as site for dimerization and cofactor interaction.¹¹Binding of a ligand to the receptor changes the dynamic behavior of PPARs helix12,suggesting that helix 12 plays an important role in PPARs activity.¹²

Expression of different genes through PPARs is controlled by complex with retinoid X receptor (RXR).¹³RXR also exist in three isoforms (α, β, and γ,) and are activated by 9-cis retinoic acid(9-cis RA).^14,15RXR binds to various retinoid like natural and synthetic ligands with varying affinity for three RXR isoform.¹⁶Formation of heterodimers with PPARs are permissive and it’s activity is regulated by either PPAR ligand or RXR ligand.^{17,18 .}Heterodimers regarded as a basic functional unit for the signaling grid rather than RXR and PPAR monomer as separate units. During dimerization both LBD and DBD are involved, but the studies on RXR/PPAR heterodimerization have mainly focused on the LBD because of their larger and stronger dimerization interface.^19,20

The binding of ligands to the PPARs make changes in the expression level of PPARs target genes encoded mRNAs and is called as ‘transactivation’.²¹ Binding of a ligand to the LBD of the PPARs changes the confirmation of structure and this binding cause the release of corepressors lead to activation of the receptor. Ligand binding domain get stabilized by releasing of the corepressor which result in the binding of coactivators such as PGC-1𝛼.²²Coreprssors repress target gene transcription²³Coactivators also form multiprotein complex which possess histone acetyltransferase (HAT) activity or methyl transferase activities.²⁴Some proliferator response elements (PPRE) are present in the promoter region of target genes and are activated by the PPAR/RXR complex. This brings RNA polymerase complex and allows gene transcription. For example, the PPREs influence insulin-sensitive genes, which enhance production of mRNAs of insulin-dependent enzymes.^25,26

Physiology of PPARs and Its subtypes:

In hepatocytes, enterocytes, monocytes/macrophages, endothelial cells, smooth muscle cells, lymphocytes and non neuronal cells like microglia and astrocytes, the expression of PPARα is found to be high. It represses proinﬂammatory responses in different cells such as microglia and astrocytes.^27,28PPARα serves as the master regulator of hepatic lipid metabolism during fasting.²⁹It activates the gene expression responsible for fatty acid movement and oxidation.³⁰PPARα is the only isoform that binds to a different types of saturated fatty acids.They are present in tissues such as liver, intestine, kidney, abdominal adipose, and skeletal muscle, tissues and are all involved in aspects of lipid metabolism. Predominantly they are present in brain.^32,33PPAR𝛽/𝛿 can bind to both saturated and unsaturated fatty acid and their binding affinity intermediate between that of PPARα and PPARγ. like Dihomo-γ linolenic acid, arachidonic acid, and EPA and eicosanoids have been shown to activate PPAR𝛽/δ.^31,34.PPAR𝛽/𝛿 mRNA and protein expression is high in neuronal cells. PPARδ has been found to decrease the expression of mediators of inflammation and adhesion molecules. Some studies proved that PPARδ ligands have the capability to inhibit cardiac hypertrophy because of their inhibitory activity on NF-κB.^35,36Three isoforms of ppar γ have been detected in human Pparℽ-1, Pparℽ-2 and Pparℽ-3.Pparℽ-1 and 3 code for the same protein while Pparℽ-2 code for a different protein. Pparℽ-1 has broad tissue distribution (heart, large and small intestines, colon, kidney, pancreas, spleen, and skeletal muscle, brain etc) Pparℽ-2 present in adipose tissue only. Pparℽ-3 found only in adipose tissue, macrophages, and colon epithelium.³⁷PPAR-γincreases the expression of a number of genes code for proteins involved in glucose and lipid metabolism.³⁸PPAR- γ has the highest expression in CNS (neurons, astrocytes, and glial cells) than other two types.²⁷

Ppar’s and Neurodegenerative Disorders:

Cognitive and Alzheimer’s like disease:

AD is chronic degenerative disease marked by memory loss and inability to function daily life.³⁹Amyloid cascade hypothesis considered as established paradigm for oxidative stress, neuroinflammation and energy dysmetabolism.⁴⁰Among the three isotypes (α, β/δ, γ), the role of PPARγ in AD is the most extensively studied, while evidences on α and β/δ are very less.⁴¹ PPARα gene expression was found to be significantly reduced in AD brains. Inhibitors of β-hydroxy β-methylglutaryl-CoA(HMG-CoA) reductase act as ligands of PPARα.statins.⁴²Binding with Leu331 and Tyr 334 residues of PPARα statins resulted in the upregulation of neurotrophins by means of PPARα mediated transcriptional activation of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) independent of the mevalonate pathway.⁴³Administration of fenofibrate into APP/PS1 transgenic mice enhanced the expression of PPARα, and decreased beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1) mRNA and protein levels, soluble amyloid precursor protein beta (sAPPβ) and amyloid-β42 (Aβ42) releases and recommended that fenofibrate may reduce the amyloidogenic processing of amyloid precursor protein (APP) in APP/PS1 transgenic mice via PPARα/phosphoinositide 3-kinase(PI3-K) pathway.⁴⁴GW7647,another PPARα agonist also reduced the expression of sAPPβ, activity of BACE-1 and Aβ42 discharge in human neuroblastoma SH-SY5Y cells transfected with APPs.This may also involved PI3-K pathway.⁴⁵The amyloid plaque diminishing action of PPARα activators (cinnamic acid and gemfibrozil) in the hippocampus in animal model of AD (5XFAD) was demonstrated by Chandra and Pahan. Moreover, they decreased neuroinflammation and thus microglia and astrocytes activation and improved spatial learning and cognition function.^46,47PPARα agonist WY14643 can inhibit the Aβ-stimulated expression of TNFα and Interleukin-6 (IL-6) reporter genes in a dose-dependent manner.⁴⁹PPARα knockdown, but not PPARβ or PPARγ, decreased the expression of ADAM10.Gemfibrozil activation of PPARα stimulated ADAM10-mediated proteolysis of APP.⁵⁰PPARα activation by Palmitoylethanolamide (PEA) prevents reactive gliosis and neuronal damage in models of Aβ neurotoxicity.⁵¹Wy14643 also prevented DNA damage and neuronal cell apoptosis induced by Aβ toxicity. PPARα activation decreased the expression and translocation of pro apoptotic proteins apoptosis-inducing factor (AIF) and endonuclease G (EndoG) in the NT2N (Post-mitotic neuronal cells) cell model. Brune S reported that PPARα polymorphism may be a risk factor for AD.⁵²

PPAR β/δ has a promoting effect on learning and memory in AD rat model.⁵³Konttinen H showed for the first time an impairment in fatty acid oxidation in human astrocytes obtained from induced pluripotent stem cells of AD patients. PPARβ/δ agonist GW0742 corrected this impairment by means of regulating an array of genes involved in cellular metabolism, increased hippocampal neurogenesis and enhanced neuronal differentiation of neuronal progenitor cells, prevented Aβ-induced impairment of long-term potentiation in hippocampal slices.⁵⁴Chronic and uncontrolled inflammatory activation of microglial cells and the secretion of nuerotoxic chemicals around the plaques serve as major reason for neuronal death in AD. Treatment of GW0742 for a short period in 5XFAD mice demonstrated, it has a prominent effect on inflammation. PPARδ activation resulted in recruitment of microglia to amyloid accumulations and increased the clearance of the plaques.⁵⁵ In a mouse model of T2DM, it has been exhibited an effect on signal transmission, synaptic plasticity, and spatial memory. It improved hippocampal long-term potentiation and also mediated enhancements in synaptic plasticity and behavior were linked with a significant recovery in hippocampal synaptic transmission.⁵⁶ Intra-hippocampal infusion of GW0742 in mice reversed Aβ1–42-induced hippocampal PPARδ down-regulation, noticeably improved Aβ1– 42-induced memory deficits. neuroinflammation by decreasing nuclear NF-κB p65, TNF-α, IL-1β and apoptotic responses indicated by decrease in cleaved caspase-3 and increased ratio of B-cell lymphoma 2(Bcl-2)/Baxin in the hippocampus.⁵⁷Barroso E reported PPARβ/δ deficiency results in cognitive impairment.⁵⁸Oral delivery of PPARβ/δ agonist significantly reduced amyloid plaque burden in the subiculum region (primary site for the amyloid plaque deposition) of 5XFAD mice. The changes in plaque burden were accompanied by increased expression of the amyloid degrading enzymes neprilysin and insulin degrading enzyme (IDE).⁵⁹Activated PPAR𝛽/𝛿 bind to PPRE found in the promoter region of suppressor of cytokine signaling1 (SOCS1) and it up-regulated the expression of SOCS1.The upregulated SOCS1 inhibits Janus Kinase 2 (JAK2)/STAT1 signalling pathway which will regulates the BACE1 expression.⁶⁰The Involvement of PPAR𝛽/𝛿 in neuronal maturation has been reported. This effect was demonstrated on rat cortical neuronal cultures by early increase in expression of microtubule-associated protein-2 (MAP-2), and growth-associated phosphoprotein-43(GAP-43).⁶¹

NSAIDs can bind with PPAR-γ thus justifying the role of NSAIDs in the treatment of AD. Heneka established that acute treatment with PPARγ agonist pioglitazone and ibuprofen reduces glial inflammation and Aβ levels in APPV717I transgenic mouse.⁶²Pioglitazone and a novel selective PPARα/γ modulator, DSP-8658, enhanced the microglial uptake of Aβ in a PPARγ dependent manner.⁶³Pioglitazone treatment also resulted in the phenotypic polarization of microglial cells from a proinflammatory microglia M1 state, into an anti-inflammatory M2 state, which was associated with enhanced phagocytosis of deposited Aβ. Induction of PPARγ increased microglial phagocytic capacity and reduced Aβ load and inflammation in high fat fed 5XFAD model.⁶⁴ Honokiol activated PPARγ and improved spatial learning and memory impairment in APPswe/PS1dE9 transgenic mouse model of AD. PPARγ activation down regulated the expression of BACE1 which in turn reduced the production of Aβ.⁶⁵Stress due to Aβ decreases heat shock protein 90 β (HSP90β) and afterward diminishes the PPARγ level results in the down-regulation of genes related to Aβ clearance in in BV2 cells and primary microglia. The treatment with a triterpene saponin Jujuboside A (JuA) maintained the stability of PPARγ in an an Axl/ERK-dependent manner, by increasing HSP90β expression in microglia and enhanced Aβ clearance.⁶⁶MicroRNAs (miRNAs), a large family of small (20-22 nucleotides) endogenous transcripts can function as key regulators in gene silencing and translational repression.⁶⁷PPARγ is a target of miR-128.Yanqiu Liu reported that miR-128 knockout or PPARγ upregulation inhibits AD-like performances, Aβ generation, APP amyloidogenic processing and inflammatory responses.⁶⁸The angiotensin II receptor blocker telmisartan has also been reported its protective role in AD partly because of PPARγ activation.⁶⁹Neuroprotectin D1’s (NPD1) anti-amyloidogenic effects are mediated in part through activation of the PPARγ receptor.⁷⁰A study of dual PPAR β/γ agonist in mild to moderate AD patients reported some limited indications on improving cognition and higher executive function and the data supported next step clinical study of T3D-959 in mild-to-moderate AD.⁷¹

Amyotrophic lateral sclerosis (ALS):

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is characterized by the degeneration of both upper and lower motor neurons, which leads to muscle weakness and eventual paralysis. Valeria proposed that during ALS progression accumulation of lipid peroxidation products at critical concentrations lead to the activation of PPARγ in motor neurons as result self-protective mechanisms get triggered by the up-regulation of lipid detoxification enzymes, such as lipoprotein lipase and glutathione S-transferase α-2. PPARγ transcriptional activity limit the damage induced by lipid peroxidation derivatives and may attenuate neurodegeneration.⁷²The PPARγ agonist pioglitazone treatment in G93A SOD1 transgenic mouse model of ALS improved motor performance, delayed weight loss, attenuated motor neuron loss, and extended survival. It also reduced iNOS, NF-κB, and 3-nitrotyrosine immunoreactivity in the spinal cords of G93A transgenic mice.⁷³ Pioglitazone also protected motor neurons against p38-mediated neuronal death and NF-κB-mediated glial inflammation in ALS transgenic mouse model.⁷⁴However, in humans, a placebo-controlled, randomized trial of pioglitazone as adjunct therapy for ALS showed no benefit in increasing survival.⁷⁵

Huntigton’s disease (HD):

HD is caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene, which encodes a polyglutamine tract in the HTT protein. Progression of HD is associated with mitochondrial dysfunction and may account for the cell-type specificity. Mutated HTT cause transcriptional dysregulation, which may lead to neuronal cell death in the brain.^76,77PGC-1α, (transcriptional dysregulation of PPARγ coactivator–1α) a co-activator that helps to regulate mitochondrial biogenesis and energy production by controlling a chain of transcriptional activities. PGC-1α was found to be upregulated several mouse models of HD and it could recover the motor phenotypes, decrease accumulation of misfolded HTT protein in the CNS and ameliorate neurodegeneration.Mijung Lee found that Beta-Lapachone can activate PGC-1α by increasing the level of Sirt-1(deacetylates PGC-1α) and CREB phosphorylation (predominant regulator of PGC-1α) and alleviated HD associated symptoms.^78,79Down regulation of PPARγ seems to play a vital role in the energy homeostasis dysregulation found in HD. Therefore PPARγ can be considered as a potential therapeutic target for this disease. Treatment with thiazolidinediones (TZD) in mouse model (R6/2) of HD expressesd improvements in progressive weight loss, motor deterioration, formation of mutant HTT aggregates, reduced expression of neuroprotective proteins such as brain-derived neurotrophic factor (BDNF) and Bcl-2. Chronic TZD treatment elevated the availability of the PPARγ protein and normalized the expression of two of its downstream genes (the glucose transporter type 4 and PPARγ coactivator-1 alpha genes).⁸⁰Mitochondrial dysfunction and oxidative stress in striatal cells that express wild-type (STHdhQ7/Q7) or mutant (STHdhQ111/Q111) huntingtin protein at physiological levels was prevented by rosiglitazone activation of PPARγ.⁸¹The chronic administration of rosiglitazone rescued BDNF deficiency in the cerebral cortex, prevented PGC-1alpha reduction and increased Sirtuin-6 (Sirt6) protein levels in N171-82Q HD mice brain.⁸²

Pan-PPAR agonist bezafibrate exerted neuroprotective effect in a transgenic mouse model of Huntington’s disease. It increased the levels of PGC-1α, PPARs and downstream genes, attenuated astrogliosis and neuronal atrophy in the striatum and increased the numbers of mitochondria. Bezafibrate also rescued lipid accumulation of brown adipose tissue in the HD mice.⁸³Activation of PPAR𝛿 by its agonistKD3010 improved motor function, reduced neurodegeneration and increased survival in mouse model of HD.PPAR𝛿 activation also decreased HTT-induced neurotoxicity in vitro and in medium of spiny-like neurons generated from stem cells derived from individuals with HD, suggesting that PPAR𝛿 activation may be a new area of treatment in HD and related disorders.⁸⁴Dickey also conducted a study with RXR agonist bexarotene in various cellular models and N171-82Q HD mouse model, found that it activates PPAR𝛿 and improve motor function, HTT protein aggregation, striatal neurodegeneartion and mouse survival.⁸⁵

Multiple sclerosis (MS)

MS is a chronic inﬂammatory disease. Inﬂammatory response in CNS leads to demyelination and neuronal injury. Self-reactive T cells are believed to initiate the disease. It is categorized under the auto-immune disease.^86,87The IL-12 family of cytokines such as IL-12, IL-23, and IL-27 play critical roles in T cell differentiation and are important modulators of MS. Jihong Xu suggested that PPARα agonist fenofibrate modulated the development of experimental autoimmune encephalomyelitis (EAE), at least in part, by suppressing the production of IL-12 family cytokines and MyD88 dependent signaling in MS model.⁸⁸Activated microglia and astrocytes are believed to contribute to disease pathology. A combination of 9-cis RA and the PPARα agonist fenoﬁbrate or gemfibrozil inhibited, TNF-α, IL-1β, IL-6 and MCP-1 production in LPS-stimulated microglia and astrocytes.^[89]Another PPARα agonist gemfibrozil can suppress relapsing remitting multiple sclerosis(RR-MS) increasing the expression of GATA-3 and decreasing the expression of T-bet through the inhibition of NO production.^90,91 PPARδ(-/-) mice develop prolonged EAE in with augmented Th1/Th17 responses, suggesting an important physiological role for PPARδ in the remission and recovery of EAE.⁹² PPAR β/δ agonists can exert protective actions in autoimmune model of demyelinating disease. Selective PPARβ/δ agonist GW0742 reduced clinical symptoms in C57BL/6 mice. GW0742 reduced astroglial and microglial inflammatory activation and IL-1β levels in EAE brain and increased expression of some myelin genes.⁹³Inhibition of 12/15-lipoxygenase by baicalein induced PPARβ/δ in microglia, and alleviated EAE in mice. Induction of PARβ/δ in the CNS, more specifically in microglia, augmentted CNS inflammation of EAE.⁹⁴PPARδ agonists GW501516 and L165041 blocked interferon (IFN)-c and IL-17 production by Th1 and Th17 cells and ameliorated MOGp35-55-induced EAE in C57BL/ 6 mice. It also decreased IL-12 and IL-23 level and an increased IL-4 and IL-10 expression in the CNS and lymphoid organs and hence suggested their use in the treatment of MS.⁹⁵

Use of RXR specific ligands may be highly effective when combined with PPARγ agonists in MS treatment.⁹⁶ 15d-PGJ2 and ciglitazone decreased IL-12 expression and differentiation of Th1 cells.⁹⁷They also showed that heterozygous PPARγ deﬁcient mice demonstrated more severe EAE than wild type mice and more severe EAE developed following treatment with PPARγ antagonists in another studies.⁹⁸Himanshu P Raikwar also reported that PPARγ agonists15d-PGJ2 and ciglitazone, inhibited EAE through blocking IL-12 signaling leading to Th1 differentiation and the PPARγ deficient heterozygous mice (PPARγ +/-) or those treated with PPARγ antagonists developed an exacerbated EAE in with an augmented Th1 response.⁹⁹15d-PGJ₂ also inhibited the proliferation of neural antigen-specific T cells from the spleen of myelin basic protein Ac_1–11 TCR-transgenic mice, which spontaneously develop EAE. It also suppressed IFN-γ, IL-10, and IL-4 production by activated lymphocytes.¹⁰⁰Heneka investigated the effects of TZDs- pioglitazone and ciglitazone and the non-TZD PPARγ agonist GW347845 on the function of peripheral blood mononuclear cells (PBMCs) from MS patients and healthy donors, all of these PPARγ agonists decreased phytohemagglutinin (PHA) induced T cell proliferation and production of the cytokines TNF-α and IFN-γ by PBMCs through decreased bcl2 expression and induced apoptosis of activated T.¹⁰¹

Parkinson’s disease (PD):

Parkinson's disease (PD) is a chronic and progressive neurodegenerative disease with multiple motor and non-motor features that contribute to the impairment of health-related quality of life (QOL), the death of dopaminergic neurons from substantia nigra pars compacta (SNPC) of basal ganglia is the central cause of PD.^102,103The ﬁrst cause of dopamine decrease is the death of dopaminergic neurons in the substantia nigra. It is possible to control progression of neuronal damage in PD by controlling oxidative stress, neuroinflammation and mitochondrial dysfunction induced by ROS generation.¹⁰⁴In brain regions such as striatum, substantia nigra, cortex and hippocampus the expression of PPARγ was found to be high.¹⁰⁵Pioglitazone protected the dopaminergic neurons in the substantia nigra of rats by reducing microglial proliferation and NFκB activation in 6-hydroxydopamine in (6-OHDA) model of PD. Pioglitazone treatment also improved motor impairment and exerted neuroprotective effects by enhancing hippocampal neurogenesis in 6-OHDA-lesioned rats.^106,107Pioglitazone inhibited the enzyme monoamine oxidase-B(MAO-B) activity which prevent conversion of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) to MPP+ and protected from MPTP-induced neurotoxicity.¹⁰⁸PPARγ activation by pioglitazone also protected neuronal cells by decreasing IκBα induction, blocking NFκB activation, iNOS induction and NO-mediated toxicity in MPTP model of PD.¹⁰⁹Pioglitazone showed some improvement in behavioral deficit on rotenone induced PD in rats and also reversed dopamine deficit in striatum.¹¹⁰Several studies using rosigliatzone also reported for its beneficial effects on PD. Rosiglitazone prevented enhanced phosphorylation of α-Syn which is a potential drug target and GSK3β at Tyr216 and also decreased αSyn oligomers in dopaminergic neurons in seipin-nKO mice.^111,112Eduardo Maria Normand showed that liposome encapsulated rosiglitazone enhanced neuroprotective effect on the retina and CNS in a rotenone-induced model of PD.¹¹³PPARγ activation by rosiglitazone increases mitochondrial biogenesis, oxygen consumption and suppresses free radical generation and autophagy in sporadic and PTEN-induced kinase 1associated PD models.¹¹⁴Another PPARγ agonist MDG548 attenuated increased microgliosis in MPTP induced PD model of mice. MDG548 has higher receptor affinity and BBB permeability than TZD.¹¹⁵Pioglitazone also reduced microglial activation and the levels of inflammatory mediators. In dopaminergic neurons it reduced nitrotyrosine expression and also significantly reducd the numbers of activated astrocytes in the striatum and substantia nigra regions of the brain. Pioglitazone protected dopaminergic neurons against LPS insult by inhibiting iNOS expression and NO generation, which is potentially mediated through inhibition of p38 MAPK activity.¹¹⁶Brage Brakedal conducted a retrospective clinical study and reported that the use of glitazones is associated with a decreased risk of incident PD in populations with diabetes.¹¹⁷

PPARδ subtype is highly expressed in hypothalamus and plays an important role maintaining homeostasis in the brain. PPARδ agonists L-165041 and GW-501516 inhibited caspase-3 activation and protected SH-SY5Y neuroblastoma cells from MPP+ mediated apoptosis and also reduced MPTP-induced dopamine depletion and its metabolites levels in the striatum region of the brain.¹¹⁸GW501516 also protected dopaminergic neurons against degeneration which reduces endoplasmic reticulum stress by IRE1α-caspase-12-mediated pathway in rotenone rat model of PD.¹¹⁹Another PPAR𝛽/𝛿 agonist GW0742 plays a role to reduce cognitive impairment associated with PD by restoring tyrosine hydroxylase levels in the brain.¹²⁰ PPAR𝛼 agonist fenofibrate, a widely used lipid lowering agent prevents dopaminergic cell loss in the SNPC and improved the striatal loss of tyrosine hydroxylase immunoreactivity in the MPTP-induced parkinsonism model of mice.¹²¹and reduced oxidative stress induced by MPTP and was confirmed by measuring the levels of glutathione peroxidas (Increased), superoxide dismutase(decreased) and hydroperoxide lipid (decreased).¹²²

CONCLUSION:

Many in vitro and in vivo studies have undergone to demonstrate the role of Peroxisome proliferator-activated receptors (PPAR) as a therapeutic target to treat various disorders. Role of three types of PPARS (PPARα, PPARβ, PPARγ) in neurodegenerative disorders such as Parkinson disease, Alzheimer’s disease, Huntington disease, Amyotrophic Lateral Sclerosis, Multiple sclerosis etc. have been studied widely. Currently available drugs provide symptomatic relief, but disease progression cannot be stopped. So drugs which can inhibit the disease progression are needed. Findings obtained from the various studies suggested that PPAR agonists can regulate several molecular pathways involved in these conditions and reduce disease progression. Current progresses of knowledge regarding the specific biological activity of PPARs in these conditions provide a foundation for the potential therapeutic use of PPAR ligands in human diseases.

CONFLICT OF INTEREST:

Authors declare no conflict of research interests.

ACKNOWLEDGEMENT:

No funding support for this study. Thanks for the KMCH College of Pharmacy and Management for the free journal access facilities.

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Received on 24.06.2020 Modified on 18.09.2020

Research J. Pharm. and Tech. 2021; 14(7):3967-3975.

DOI: 10.52711/0974-360X.2021.00688