Posttranscriptional regulation of Nrf2 through miRNAs and their role in Alzheimer's disease.

The nuclear factor erythroid-derived 2-related factor 2 (NFE2L2/Nrf2) is a pivotal facilitator of cytoprotective responses against the oxidative/electrophilic insults. Upon activation, Nrf2 induces transcription of a wide range of cytoprotective genes having antioxidant response element (ARE) in their promoter region. Dysfunction in Nrf2 signaling has been linked to the pathogenesis of AD and several studies have suggested that boosting Nrf2 expression/activity by genetic or pharmacological approaches is beneficial in AD. Among the diverse mechanisms that regulate the Nrf2 signaling, miRNAs-mediated regulation of Nrf2 has gained much attention in recent years. Several miRNAs have been reported to directly repress the post-transcriptional expression of Nrf2 and thereby negatively regulate the Nrf2-dependent cellular cytoprotective response in AD. Moreover, several Nrf2 targeting miRNAs are misregulated in AD brains. This review is focused on the role of misregulated miRNAs that directly target Nrf2, in AD pathophysiology. Here, alongside a general description of functional interactions between miRNAs and Nrf2, we have reviewed the evidence indicating the possible role of these miRNAs in AD pathogenesis.

Therapeutic potential of pharmacological agents targeting TRP channels in CNS disorders.

Central nervous system (CNS) disorders like Alzheimer's disease (AD), Parkinson disease (PD), stroke, epilepsy, depression, and bipolar disorder have a high impact on both medical and social problems due to the surge in their prevalence. All of these neuronal disorders share some common etiologies including disruption of Ca2+ homeostasis and accumulation of misfolded proteins. These misfolded proteins further disrupt the intracellular Ca2+ homeostasis by disrupting the activity of several ion channels including transient receptor potential (TRP) channels. TRP channel families include non-selective Ca2+ permeable channels, which act as cellular sensors activated by various physio-chemical stimuli, exogenous, and endogenous ligands responsible for maintaining the intracellular Ca2+ homeostasis. TRP channels are abundantly expressed in the neuronal cells and disturbance in their activity leads to various neuronal diseases. Under the pathological conditions when the activity of TRP channels is perturbed, there is a disruption of the neuronal homeostasis through increased inflammatory response, generation of reactive oxygen species, and mitochondrial dysfunction. Therefore, there is a potential of pharmacological interventions targeting TRP channels in CNS disorders. This review focuses on the role of TRP channels in neurological diseases; also, we have highlighted the current insights into the pharmacological modulators targeting TRP channels.

Heme oxygenase-1, a novel target for the treatment of diabetic complications: focus on diabetic peripheral neuropathy.

Diabetic neuropathy is a complex disorder induced by long standing diabetes. Many signaling pathways and transcription factors have been proposed to be involved in the development and progression of related processes. Years of research points to critical role of oxidative stress, neuroinflammation and apoptosis in the pathogenesis of neuropathy in diabetes. Heme oxygenase-1 (HO-1) is heat-shock protein induced under conditions of different kinds of stress and has been implicated in cellular defense against oxidative stress. HO-1 degrades heme to biliverdin, carbon monoxide (CO) and free iron. Biliverdin and CO are gaining particular interest because these two have been found to mediate most of anti-inflammatory, antioxidant and anti-apoptotic effects of HO-1. Although extensively studied in different kinds of cancers and cardiovascular conditions, role of HO-1 in diabetic neuropathy is still under investigation. In this paper, we review the unique therapeutic potential of HO-1 and its role in mitigating various pathological processes that lead to diabetic neuropathy. This review also highlights the therapeutic approaches such as pharmacological and natural inducers of HO-1, gene delivery of HO-1 or its reaction products that in future, could lead to progression of HO-1 activators through the preclinical stages of drug development to clinical trials.

Biological evaluation and structural insights for design of subtype-selective peroxisome proliferator activated receptor-α (PPAR-α) agonists.

Peroxisome proliferator activated receptors-α (PPAR-α) control the expression of several genes involved in diseases like diabetes, hyperlipidaemia, and inflammatory disorders. Herein, we report the biological evaluation of recently identified hits from pharmacophore based virtual screening. The most potent hits, ZINC17167211, ZINC06472206 and ZINC08438472 showed EC50 values of 0.16, 1.1 and 12.1nM in PPAR-α agonist assay, respectively. Further, comparative docking and molecular dynamics analysis of selective PPAR-α agonists revealed that Thr279, Ala333, Lys358 and Met325 residues play an important role in the selective PPAR-α agonistic activity. The insights from docking and molecular dynamic studies will serve as a guideline for the development of potent and selective PPAR-α agonists.

Synthesis of CNS active thyrotropin-releasing hormone (TRH)-like peptides: Biological evaluation and effect on cognitive impairment induced by cerebral ischemia in mice.

Thyrotropin-releasing hormone (TRH)-like peptides were synthesized by replacing critical histidine and pGlu residues in the native peptide. The peptides were evaluated in vitro for receptor binding activity assay and in the cell functional assay; the peptides exhibit selective basal signaling agonist behavior toward TRH-R2. For example, peptides 8a, 8b, 8c, 8 f, 8 h, 8 l and 12 d activated TRH-R2 with potency (EC50) of 0.53 µM, 0.048 µM, 0.05 µM, 0.006 µM, 0.31 µM, 0.034 µM and 0.004 µM, respectively. In contrast for signaling activation of TRH-R1, the same peptide required higher concentration of 19.35 µM, 3.98 µM, 2.54 µM, 0.287 µM, 11.28 µM, 0.986 µM and 0.944 µM, respectively. The results showed that peptides were 36.5, 82.9, 50.8, 47.8, 36.3, 32.6 and 235-fold selective to TRH-R2 receptor subtype. The peptides were investigated for CNS activity at 10 µmol/kg in pentobarbital-induced sleep assay study. Peptides 8c (16.5 ± 1.4 min) and 8l (16.5 ± 2.1 min) displayed excellent CNS activity. In an in vivo study, peptide 8c did not cause significant change in the rat plasma TSH levels. The peptide 8c was further investigated for neuroprotective potential, and significantly reduced infracts volume and neurological score in the focal cerebral ischemia model in mice. Peptide 8c also significantly lowered MDA levels, indicating reduction of oxidative and enhanced percentage cell survival in CA1 region, when compared to ischemic brain.

Diabetic-induced increased sodium channel activity attenuated by tetracaine in sensory neurons in vitro.

The present study was aimed to explore correlation between the altered pain perception and Na(+) channel activity in diabetic animals as well as the effect of tetracaine on sensory neurons of diabetic rat. In streptozotocin-induced diabetic rats behavioral nociceptive parameters were assessed. The Na(+) current (INa) was obtained using whole-cell voltage-clamp configuration in dorsal root ganglion (DRG) neurons isolated from diabetic rat (in vitro). In addition, the effects of tetracaine on altered Na(+) channel activity associated with diabetes in small DRG neurons were evaluated. After induction of diabetes mechanical allodynia, thermal hyperalgesia and Na(+) channel activity were altered significantly in 4th and 6th week in relation to the control. Altered pain parameters were in correlation with increased INa in time-dependent manner. In comparison to age-matched control (-1.10±0.20nA) the INa was found to be -2.49±0.21nA at 4th week and -3.71±0.28nA at 6th week. The increased activity of Na(+) channels was blocked by tetracaine even in diabetic condition. The depression of the INa on tetracaine exposure was not sensitive to the voltage or time. The conductance curve shifted towards right around -8.0mV. The alterations in neuropathic pain associated with diabetes and Na(+) channel activity has been clearly correlated in time-dependent manner. The INa density was increased significantly with the progression of neuropathic pain. Local anesthetic, tetracaine potentially blocked the Na(+) channel activity in diabetic sensory neurons.

Scrub Typhus: An Acute Precipitant for Acute on Chronic Liver Failure.

Acute-on-chronic liver failure (ACLF) is a clinical syndrome with high mortality. Many acute precipitating factors have been implicated in triggering the acute event of ACLF, with bacterial infections being a common precipitant. However, many other precipitants can cause ACLF; therefore, identification of these factors early in the golden window and their treatment can result in improved prognosis. Scrub typhus usually presents as uncomplicated acute febrile illness but rarely as complicated. Few case reports of scrub-typhus-induced acute liver failure have been reported but none with scrub-typhus-precipitating ACLF so far. Therefore, we are reporting a case of scrub-typhus-precipitating ACLF, where timely intervention with antibiotics results in improved outcome.

Ion Channels and Metal Ions in Parkinson's Disease: Historical Perspective to the Current Scenario.

Parkinson's disease (PD) is a neurodegenerative condition linked to the deterioration of motor and cognitive performance. It produces degeneration of the dopaminergic neurons along the nigrostriatal pathway in the central nervous system (CNS), which leads to symptoms such as bradykinesias, tremors, rigidity, and postural instability. There are several medications currently approved for the therapy of PD, but a permanent cure for it remains elusive. With the aging population set to increase, a number of PD cases are expected to shoot up in the coming times. Hence, there is a need to look for new molecular targets that could be investigated both preclinically and clinically for PD treatment. Among these, several ion channels and metal ions are being studied for their effects on PD pathology and the functioning of dopaminergic neurons. Ion channels such as N-methyl-D-aspartate (NMDA), γ-aminobutyric acid A (GABAA), voltage-gated calcium channels, potassium channels, HCN channels, Hv1 proton channels, and voltage-gated sodium channels and metal ions such as mercury, zinc, copper, iron, manganese, calcium, and lead showed prominent involvement in PD. Pharmacological agents have been used to target these ion channels and metal ions to prevent or treat PD. Hence, in the present review, we summarize the pathophysiological events linked to PD with an emphasis on the role of ions and ion channels in PD pathology, and pharmacological agents targeting these ion channels have also been listed.

Supplementation of probiotic Bifidobacterium breve Bif11 reverses neurobehavioural deficits, inflammatory changes and oxidative stress in Parkinson's disease model.

Human gut microbiota are thought to affect different physiological processes in the body, including brain functions. Gut dysbiosis has been linked to the progression of Parkinson's disease (PD) and thus, restoring the healthy gut microbiota with supplementation of putative probiotic strains can confer some benefits in PD. In the current study, we explored the neuroprotective potential of Bifidobacterium breve Bif11 supplementation in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) treated female Sprague Dawley rats. This study investigated the behavioural, molecular and biochemical parameters in the MPTP rat model. A pharmacological intervention of Bif11 at doses of 1 × 1010 CFU and 2 × 1010 CFU for 21 days was found to attenuate the cognitive and motor changes in the MPTP rat model. Furthermore, it also increased the tyrosine hydroxylase levels, reduced pro-inflammatory markers and decreased oxidative and nitrosative stress in the mid brain of MPTP-lesioned rats. Bif11 supplementation even restored the levels of short-chain fatty acids and decreased intestinal epithelial permeability in MPTP-induced PD model rats. In summary, these findings demonstrate that B. breve Bif11 has the potential to ameliorate symptoms of PD. However, this therapy needs to be further investigated with in-depth mechanistic insights in the future for the treatment of PD.

SNEDDS curcumin formulation leads to enhanced protection from pain and functional deficits associated with diabetic neuropathy: an insight into its mechanism for neuroprotection.

Curcumin has shown to be effective against various diabetes related complications. However major limitation with curcumin is its low bioavailability. In this study we formulated and characterized self nano emulsifying drug delivery system (SNEDDS) curcumin formulation to enhance its bioavailability and then evaluated its efficacy in experimental diabetic neuropathy. Bioavailability studies were performed in male Sprague Dawley rats. Further to evaluate the efficacy of formulation in diabetic neuropathy various parameters like nerve function and sensorimotor perception were assessed along with study of inflammatory proteins (NF-κB, IKK-ß, COX-2, iNOS, TNF-α and IL-6). Nanotechnology based formulation resulted in prolonged plasma exposure and bioavailability. SNEDDS curcumin provided better results against functional, behavioural and biochemical deficits in experimental diabetic neuropathy, when compared with naive curcumin. Further western blot analysis confirmed the greater neuroprotective action of SNEDDS curcumin. SNEDDS curcumin formulation due to higher bioavailability was found to afford enhanced protection in diabetic neuropathy. FROM THE CLINICAL EDITOR: In this study the authors formulated and characterized a self-emulsifying drug delivery system for formulation to enhance curcumin bioavailability in experimental diabetic neuropathy. Enhanced efficacy was demonstrated in a rat model.

Cerebral venous sinus thrombosis following ChAdOx1 nCoV-19 AstraZeneca COVID-19 vaccine.

A woman in her mid-twenties was admitted with headache, ultimately leading to a diagnosis of cerebral venous sinus thrombosis 10 days after receiving a first dose of the AstraZeneca ChAdOx1 nCoV-19 vaccine (Vaxzevria). We report this case from clinical investigations to outcomes and discuss the issues raised by it regarding the ChAdOx1 nCoV-19 vaccine.

Bifidobacterium breve Bif11 supplementation improves depression-related neurobehavioural and neuroinflammatory changes in the mouse.

Gut dysbiosis has been closely linked to the onset and progression of several brain-related disorders such as depression. The administration of microbiota-based formulations such as probiotics helps restore healthy gut flora and plays a role in preventing and treating depression-like behavior. Therefore, we evaluated the efficacy of probiotic supplementation using our recently isolated putative probiotic Bifidobacterium breve Bif11 in ameliorating lipopolysaccharide (LPS)-induced depression-like behavior in male Swiss albino mice. Mice were fed orally with B. breve Bif11 (1 × 1010 CFU and 2 × 1010 CFU) for 21 days before being challenged with a single intraperitoneal LPS injection (0.83 mg/kg). Behavioral, biochemical, histological and molecular analysis were done with an emphasis on inflammatory pathways linked to depression-like behavior. Daily supplementation with B. breve Bif11 for 21 days prevented the onset of depression-like behavior induced by LPS injection, besides reducing the levels of inflammatory cytokines such as matrix metalloproteinase-2, c-reactive protein, interleukin-6, tumor necrosis factor-alpha and nuclear factor kappa-light-chain-enhancer of activated B cells. It also prevented the decrease of the brain-derived neurotrophic factor levels and neuronal cell viability in the prefrontal cortex of LPS-treated mice. Furthermore, we observed that gut permeability was reduced, there was an improved short-chain fatty acid profile and reduced gut dysbiosis in the LPS mice fed with B. breve Bif11. Similarly, we observed a decrease in behavioural deficits and restoration of gut permeability in chronic mild stress. Together, these results would help in deciphering the role of probiotics in the management of neurological disorders where depression, anxiety and inflammation are prominent clinical features.

Current perspectives on potential role of albumin in neuroprotection.

Albumin is the most abundant plasma protein synthesised mainly in the liver. It is also a major component of extracellular fluids including cerebrospinal fluid, interstitial fluid and lymph. Albumin has several biochemical properties including regulation of colloid osmotic pressure of plasma, transportation of hormones, fatty acids, drugs and metabolites across plasma, regulation of microvascular permeability, antioxidant activity, anti-thrombotic activity and anti-inflammatory activity. This multifunctional protein has been implicated in many neurological diseases owing to its ability to regulate hemodynamic properties of the brain circulation as well as the direct neuroprotective actions on neuronal and glial cells. In this review, we summarise various neuroprotective actions of the albumin in the brain. In experimental ischemic stroke, exogenous human serum albumin administration has been found to be neuroprotective via reducing brain swelling, prevention of post-ischemic thrombosis, anti-oxidant activity, hemodilution and increasing the perfusion to the ischemic tissue. Also, human serum albumin administration is currently under clinical trials for treatment of cerebral ischemia. In the experimental models of Alzheimer's disease, albumin has been implicated in neuroprotection by inhibiting polymerisation and enhancing the clearance of amyloid ß. The direct neuroprotective actions on neuronal and glial cells are mediated via endogenously produced albumin or cellular uptake of blood derived albumin. These neuroprotective effects of albumin are partly attributed to anti-oxidant property and modulation of intracellular signalling of neuronal or glial cells. The recent finding of de novo synthesis of albumin in microglial cells directs us to explore newer roles of this endogenously produced multifunctional protein in normal as well as pathological conditions of the brain.

Oxidative stress and Nrf2 in the pathophysiology of diabetic neuropathy: old perspective with a new angle.

Long-standing diabetes and complications thereof particularly, neuropathy stands for one of the major causes of morbidity across the globe. It is postulated that excessive production of reactive oxygen species is a key component in the development and progression of diabetic neuropathy. Oxidative damage is the most common concluding pathway for various pathogenetic mechanisms of neuronal injury in diabetic neuropathy. However despite optimistic preclinical data, it is still very ambiguous that why antioxidants have failed to demonstrate significant neuroprotection in humans. A growing body of evidences now suggests that strategies utilizing a more targeted approach like focusing on Nrf2 (a transcription factor modulating oxidative stress) may provide an enthralling avenue to optimize neuroprotection in diabetes and diabetic neuropathy. This review presents an emerging concept of Nrf2 in diabetic neuropathy; thus looking forward to newer strategies for combating the oxidant induced damage.

Melatonin modulates neuroinflammation and oxidative stress in experimental diabetic neuropathy: effects on NF-κB and Nrf2 cascades.

Melatonin exhibits an array of biological activities, including antioxidant and anti-inflammatory actions. Diabetic neuropathy is one of the complications of diabetes with a prevalence rate of 50-60%. We have previously reported the protective effect of melatonin in experimental diabetic neuropathy. In this study, we investigated the role of nuclear factor-kappa B (NF-κB) and nuclear erythroid 2-related factor 2 (Nrf2) in melatonin-mediated protection against streptozotocin-induced diabetic neuropathy. Melatonin at doses of 3 and 10 mg/kg was administered daily in seventh and eighth week after diabetes induction. Motor nerve conduction velocity and nerve blood flow were improved in melatonin-treated animals. Melatonin also reduced the elevated expression of NF-κB, IκB-α, and phosphorylated IκB-α. Further, melatonin treatment also reduced the elevated levels of proinflammatory cytokines (TNF-α and IL-6), iNOS and COX-2 in sciatic nerves of animals. The capacity of melatonin to modulate Nrf2 pathway was associated with increased heme oxygenase-1 (HO-1) expression, which strengthens antioxidant defense. This fact was also established by decreased DNA fragmentation (because inhibition of excessive oxidant-induced DNA damage) in the sciatic nerve of melatonin-treated animals. The results of this study suggest that melatonin modulates neuroinflammation by decreasing NF-κB activation cascade and oxidative stress by increasing Nrf2 expression, which might be responsible at least in part, for its neuroprotective effect in diabetic neuropathy.

SARS-CoV-2 antibody seroprevalence in NHS healthcare workers in a large double-sited UK hospital.

We determined the seroprevalence of SARS-CoV-2 antibodies in NHS healthcare workers (HCWs) in a cross-sectional study from a large general hospital located in a double-sited rural and semi-rural area. The sample size of 3,119 HCWs (mean age 43±13) consisted of 75.2% women, 61.1% White individuals and predominantly (62.4%) asymptomatic individuals. Seroprevalence of SARS-CoV-2 antibodies was 19.7%. Determinants of seropositivity were preceding symptomatic infection and non-White ethnicity. Regardless of staff role or sex, multivariate regression analysis revealed that non-White HCWs were three times (odds ratio [OR] 3.12, 95% confidence interval [CI] 2.53-3.86, P<0.001) more likely to have antibodies than White staff, and seven times (OR 7.10, 95% CI 5.72-8.87, P<0.001) more likely if there was a history of preceding symptoms. We report relatively high rates of seropositivity in all NHS healthcare workers. Non-White symptomatic HCWs were significantly more likely to be seropositive than their colleagues, independent of age, sex or staff role.

Allicin, a dietary trpa1 agonist, prevents high fat diet-induced dysregulation of gut hormones and associated complications.

Scope. Given the global epidemic of diabesity (co-existence of both diabetes and obesity), novel approaches that target gut hormone secretion and their modulation may offer the dual benefits of increased efficacy and limited side effects. In the present study, we tested the hypothesis that agonism of Transient Receptor Potential Ankyrin 1 (TRPA1), using a dietary activator, has a modulatory role in high fat diet (HFD)-induced dysregulation of post-prandial gut hormone responses and prevention of metabolic alterations. Methods and results. The effect of HFD on TRPA1 expression in different parts of the gut using immunohistochemistry, western blotting and RT-PCR was studied. Dietary TRPA1 agonist, Allicin Rich Garlic Juice (ARGJ), was co-administered along with HFD in mice for three months and various metabolic health parameters, relative gut hormone levels and inflammation were observed. The HFD caused substantial reduction in gut TRPA1 expression along with dysregulation in post-prandial normalization of gut hormone levels, particularly GLP-1, precipitating hunger phenotype, altered glucose homeostasis, hepatic inflammation and fat accumulation. TRPA1 agonism through ARGJ co-supplementation prevented HFD-induced dysregulation in post-prandial normalization of gut hormone levels and averted metabolic and inflammatory complications in peripheral tissues. Conclusion. Our findings provide evidence that ARGJ (diet-based TRPA1 agonism) can be employed as a feasible strategy, as nutraceuticals or food, to prevent HFD-induced metabolic complications.

NF-kappaB inhibitory action of resveratrol: a probable mechanism of neuroprotection in experimental diabetic neuropathy.

Resveratrol has shown array of biological actions, and is under clinical development for various disease conditions. The etiology of diabetic neuropathy revolves around oxidative stress, AGE formation, lipid peroxidation etc. All these stimulate inflammatory processes and NF-kappaB cascade is considered as one of the major players of inflammatory response. Activation of NF-kappaB results in elevated levels of inflammatory mediators. COX-2 and TNF-alpha activity have also been correlated with inflammatory damage in the pathophysiology of diabetic neuropathy (DN). Therefore we investigated the effect of resveratrol on NF-kappaB inflammatory cascade, COX-2, TNF-alpha and IL-6 levels in experimental DN. We found that resveratrol protected against various functional and behavioral deficits in diabetic neuropathy in line with our earlier published reports. In this study we found that the resveratrol treatment decreased the expression of p65 and IkappaB-alpha in treated rats. Treatment also ameliorated the elevated levels of TNF-alpha, IL-6 and COX-2. Resveratrol treatment produced significant decrease in nerve MDA levels in treated animals which may also be contributing to reduction in neuro-inflammation. This study confirms the NF-kappaB inhibitory activity and anti-inflammatory activity of resveratrol which may contribute to neuroprotection in diabetic neuropathy apart from its antioxidant effect.

Concurrent targeting of nitrosative stress-PARP pathway corrects functional, behavioral and biochemical deficits in experimental diabetic neuropathy.

Peroxynitrite mediated nitrosative stress, an indisputable initiator of DNA damage and overactivation of poly(ADP-ribose) polymerase (PARP), a nuclear enzyme activated after sensing DNA damage, are two crucial pathogenetic mechanisms in diabetic neuropathy. The intent of the present study was to investigate the effect of combination of a peroxynitrite decomposition catalyst (PDC), FeTMPyP and a PARP inhibitor, 4-ANI against diabetic peripheral neuropathy. The end points of evaluation of the study included motor nerve conduction velocity (MNCV) and nerve blood flow (NBF) for evaluating nerve functions; thermal hyperalgesia and mechanical allodynia for assessing nociceptive alterations, malondialdehyde and peroxynitrite levels to detect oxidative stress-nitrosative stress; NAD concentration in sciatic nerve to assess overactivation of PARP. Additionally immunohistochemical studies for nitrotyrosine and Poly(ADP-ribose) (PAR) was also performed. Treatment with the combination of FeTMPyP and 4-ANI led to significant improvement in nerve functions and pain parameters and also attenuated the oxidative-nitrosative stress markers. Further, the combination also reduced the overactivation of PARP as evident from increased NAD levels and decreased PAR immunopositivity in sciatic nerve microsections. Thus, it can be concluded that treatment with the combination of a PDC and PARP inhibitor attenuates alteration in peripheral nerves in diabetic neuropathy (DN).

Peroxisome proliferator-activated receptor gamma agonists as neuroprotective agents.

Peroxisome proliferator-activated receptor gamma (PPARgamma) has already been considered as an attractive therapeutic target for the treatment of metabolic disorders. Recently, PPARgamma agonists were shown to effectively attenuate oxidative stress, inflammation and apoptosis in the central nervous system. There are several preclinical and clinical studies indicating neuroprotective potential of PPARgamma agonists in the treatment of cerebral ischemia, Parkinson's disease, Alzheimer's disease, multiple sclerosis and amyotrophic lateral sclerosis. In these disorders, apart from inhibiting oxidative stress, inflammation and apoptosis, PPARgamma agonists have the potential to modulate various signaling molecules/pathways, including matrix metalloproteinase-9, mitogen-activated protein kinases, signal transducer and activator of transcription, mitochondrial uncoupling protein 2, mitoNEET expression, amyloid precursor protein degradation, beta-site amyloid precursor protein cleaving enzyme 1 and Wnt signaling. This article discusses evidence and mechanisms supporting the neuroprotective effects of PPARgamma agonists in central nervous system disorders.