Experimental Type 2 diabetes and lipotoxicity-associated neuroinflammation involve mitochondrial DNA-mediated cGAS/STING axis: implication of Type-1 interferon response in cognitive impairment.

Type-1 IFN (interferon)-associated innate immune response is increasingly getting attention in neurodegenerative and metabolic diseases like type 2 diabetes (T2DM). However, its significance in T2DM/lipotoxicity-induced neuroglia changes and cognitive impairment is missing. The present study aims to evaluate the involvement of cGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon gene), IRF3 (interferon regulatory factor-3), TBK (TANK binding kinase)-mediated Type-1 IFN response in the diabetic brain, and lipotoxicity (palmitate-bovine serum albumin conjugate/PA-BSA)-induced changes in cells (neuro2a and BV2). T2DM was induced in C57/BL6 mice by feeding on a high-fat diet (HFD, 60% Kcal) for 16 weeks and injecting a single dose of streptozotocin (100 mg/kg, i.p) in the 12th week. Plasma biochemical parameter analysis, neurobehavioral assessment, protein expression, and quantitative polymerase chain reaction study were carried out to decipher the hypothesis. T2DM-associated metabolic and lipotoxic stress led to mitochondrial impairment causing leakage of mtDNA to the cytoplasm further commencing cGAS activation and its downstream signaling. The diseased hippocampus and cortex showed decreased expression of synaptophysin (p < 0.01) and PSD-95 (p < 0.01, p < 0.05) with increased expression of cGAS (p < 0.001), p-STING (p < 0.001), p-STAT1 (signal transducer and activator of transcription) (p < 0.01), and IFN-ß (p < 0.001) compared to normal control. The IFN-ß/p-STAT1-mediated microglia activation was executed employing a conditioned media approach. C-176, a selective STING inhibitor, alleviated cGAS/p-STING/IFN-ß expression and proinflammatory microglia/M1-associated markers (CD16 expression, CXCL10, TNF-α, IL-1ß mRNA fold change) in the diabetic brain. The present study suggests Type-1IFN response may result in neuroglia dyshomeostasis affecting normal brain function. Alleviating STING signaling has the potential to protect T2DM-associated central ailment.

S1PR2 inhibition mitigates cognitive deficit in diabetic mice by modulating microglial activation via Akt-p53-TIGAR pathway.

Cognitive deficit is one of the challenging complications of type 2 diabetes. Sphingosine 1- phosphate receptors (S1PRs) have been implicated in various neurodegenerative and metabolic disorders. The association of S1PRs and cognition in type 2 diabetes remains elusive. Microglia-mediated neuronal damage could be the thread propagating cognitive deficit. The effects of S1PR2 inhibition on cognition in high-fat diet and streptozotocin-induced diabetic mice were examined in this work. We further assessed microglial activation and putative microglial polarisation routes. Cognitive function loss was observed after four months of diabetes induction in Type 2 diabetes animal model. JTE013, an S1PR2 inhibitor, was used to assess neuroprotection against cognitive decline and neuroinflammation in vitro and in vivo diabetes model. JTE013 (10 mg/kg) improved synaptic plasticity by upregulating psd95 and synaptophysin while reducing cognitive decline and neuroinflammation. It further enhanced anti-inflammatory microglia in the hippocampus and prefrontal cortex (PFC), as evidenced by increased Arg-1, CD206, and YM-1 levels and decreased iNOS, CD16, and MHCII levels. TIGAR, TP53-induced glycolysis and apoptosis regulator, might facilitate the anti-inflammatory microglial phenotype by promoting oxidative phosphorylation and decreasing apoptosis. However, since p53 is a TIGAR suppressor, inhibiting p53 could be beneficial. S1PR2 inhibition increased p-Akt and TIGAR levels and reduced the levels of p53 in the PFC and hippocampus of type 2 diabetic mice, thereby decreasing apoptosis. In vitro, palmitate was used to imitate sphingolipid dysregulation in BV2 cells, followed by conditioned media exposure to Neuro2A cells. JTE013 rescued the palmitate-induced neuronal apoptosis by promoting the anti-inflammatory microglia. In the present study, we demonstrate that the inhibition of S1PR2 improves cognitive function and skews microglia toward anti-inflammatory phenotype in type 2 diabetic mice, thereby promising to be a potential therapy for neuroinflammation.

Fingolimod exerts neuroprotection by regulating S1PR1 mediated BNIP3-PINK1-Parkin dependent mitophagy in rotenone induced mouse model of Parkinson's disease.

The motor impairments brought on by the loss of dopaminergic neurons in the substantia nigra are the most well-known symptoms of Parkinson's disease (PD). It is believed that dopaminergic neurons are especially vulnerable to mitochondrial malfunction. For the maintenance of mitochondrial integrity, selective autophagic removal of dysfunctional mitochondria via mitophagy primarily regulated by PINK1/Parkin pathway is essential. Moreover, newer studies also implicate the role of phospholipid metabolism, such as that of Sphingosine-1-phosphate (S1P) as a contributor to PD. S1P receptors have been reported to influence mitochondrial function in neurodegenerative diseases. Fingolimod (FTY720), an S1P receptor-1 modulator has been proven effective in PD but its regulation of mitophagy in PD is still elusive. In this study, the neuroprotective effect of FTY720 by modulating mitophagy, has been explored against rotenone (ROT) induced neurotoxicity in in-vivo. The animals were randomly divided into 5 groups namely, Normal Control (NC); Disease control (DC): ROT (1.5 mg/kg); Low dose (LD): ROT + FTY720 (0.5 mg/kg); High dose (HD): ROT + FTY720 (1 mg/kg) and Vehicle control (VC): 1 % DMSO. ROT was administered through i.p. and FTY720 through p.o. for 21 days. At the end of the study, various neurobehavioral studies (rotarod test and actimeter), western blot techniques, and immunofluorescence studies were performed. FTY720 restored the neurobehavioural functions and protein expression of PINK1, Parkin and BNIP3 in ROT-induced PD mice. The results obtained in our study suggest that FTY720 has a neuroprotective effect in ROT-induced mice model of PD via PINK1-Parkin mediated mitophagy.

Development of trisubstituted thiophene-3-arboxamide selenide derivatives as novel EGFR kinase inhibitors with cytotoxic activity.

Overexpression of EGFR is one of the eminent oncogenic drivers detected in the development of several human cancers. The increasing incidences of mutation-based resistance in the tyrosine kinase domain call upon the need for the development of a newer class of small-molecule TK inhibitors. Accordingly, a new series of symmetrical trisubstituted thiophene-3-carboxamide selenide derivatives was developed via the hybridization of complementary pharmacophores. Most of the compounds showed a modest to excellent antiproliferative action at 20 µM concentration. The utmost antiproliferative activity was portrayed by compound 16e on the selected cancer cell lines with IC50 < 9 µM, the lowest being 3.20 ± 0.12 µM in the HCT116 cell line. Further, it also displayed an impressive EGFR kinase inhibition with an IC50 value of 94.44 ± 2.22 nM concentration. As a corollary of the reported EGFR inhibition, the nature, energy, and stability of the binding interactions were contemplated via in silico studies.

Dimethyl fumarate ameliorates parkinsonian pathology by modulating autophagy and apoptosis via Nrf2-TIGAR-LAMP2/Cathepsin D axis.

Mounting evidence suggests a role for oxidative stress and accumulation of dysfunctional organelle and misfolded proteins in PD. Autophagosomes mediate the clearance of these cytoplasmic proteins via delivery to lysosomes to form autophagolysosomes, followed by degradation of the protein by lysosomal enzymes. In PD, autophagolysosome accumulation occurs initiating a plethora of events resulting in neuronal death by apoptosis. This study evaluated the effect of Dimethylfumarate (DMF), an Nrf2 activator in the rotenone-induced mouse PD model. In PD mice, there was decreased expression of LAMP2 and LC3, which resulted in inhibition of autophagic flux and increased expression of cathepsin D, which mediated apoptosis. The role of Nrf2 activation in alleviating oxidative stress is well known. Our study elucidated the novel mechanism underlying the neuroprotective effect of DMF. The loss of dopaminergic neurons induced by rotenone was lessened to a significant extent by pre-treatment with DMF. DMF promoted autophagosome formation and inhibited apoptosis by removing the inhibitory effect of p53 on TIGAR. TIGAR expression upregulated LAMP2 expression and downregulated Cathepsin D, promoting autophagy and inhibiting apoptosis. Thus, it was proved that DMF confers neuroprotection against rotenone-induced dopaminergic neurodegeneration and could be used as a potential therapeutic agent for PD and its progression.

Sphingosine 1 phosphate lyase inhibition rescues cognition in diabetic mice by promoting anti-inflammatory microglia.

Sphingosine-1-phosphate (S1P) is emerging as a crucial sphingolipid modulating neuroinflammation and cognition. S1P levels in the brain have been found to be decreased in cognitive impairment. S1P lyase (S1PL) is the key enzyme in metabolizing S1P and has been implicated in neuroinflammation. This study evaluated the effect of S1PL inhibition on cognition in type 2 diabetic mice. Fingolimod (0.5 mg/kg and 1 mg/kg) rescued cognition in high-fat diet and streptozotocin-induced diabetic mice, as evident in the Y maze and passive avoidance test. We further evaluated the effect of fingolimod on the activation of microglia in the pre-frontal cortex (PFC) and hippocampus of diabetic mice. Our study revealed that fingolimod inhibited S1PL and promoted anti-inflammatory microglia in both PFC and hippocampus of diabetic mice as it increased Ym-1 and arginase-1. The levels of p53 and apoptotic proteins (Bax and caspase-3) were elevated in the PFC and hippocampus of type 2 diabetic mice which fingolimod reversed. The underlying mechanism promoting anti-inflammatory microglial phenotype was also explored in this study. TIGAR, TP53-associated glycolysis and apoptosis regulator, is known to foster anti-inflammatory microglia and was found to be downregulated in the brain of type 2 diabetic mice. S1PL inhibition decreased the levels of p53 and promoted TIGAR, thereby increasing anti-inflammatory microglial phenotype and inhibiting apoptosis in the brain of diabetic mice. Our study reveals that S1PL inhibition could be beneficial in mitigating cognitive deficits in diabetic mice.

Necrostatin-1S mitigates type-2 diabetes-associated cognitive decrement and lipotoxicity-induced neuro-microglia changes through p-RIPK-RIPK3-p-MLKL axis.

Type-2 diabetes mellitus (T2DM) is associated with neuroinflammation and cognitive decrement. Necroptosis programmed necrosis is emerging as the major contributing factor to central changes. It is best characterized by the upregulation of p-RIPK(Receptor Interacting Kinase), p-RIPK3, and the phosphorylated-MLKL (mixed-lineage kinase domain-like protein). The present study aims to evaluate the neuroprotective effect of Necrostatin (Nec-1S), a p-RIPK inhibitor, on cognitive changes in the experimental T2DM model in C57BL/6 mice and lipotoxicity-induced neuro-microglia changes in neuro2A and BV2 cells. Further, the study also explores whether Nec-1S would restore mitochondrial and autophago-lysosomal function.T2DM was developed in mice by feeding them a high-fat diet (HFD) for 16 weeks and injecting a single dose of streptozotocin (100 mg/kg, i.p) on the 12th week. Nec-1S was administered for 3 weeks at (10 mg/kg, i.p) once every 3 days. Lipotoxicity was induced in neuro2A, and BV2 cells using 200 µM palmitate/bovine serum albumin conjugate. Nec-1S (50 µM), and GSK-872(10 µM) were further used to explore their relative effect. The neurobehavioral performance was assessed using mazes and task-assisted performance tests. To decipher the hypothesis plasma parameters, western blot, immunofluorescence, microscopy, and quantitative reverse transcription-PCR studies were carried out. The Nec-1S treatment restored cognitive performance and reduced the p-RIPK-p-RIPK3-p-MLKL mediated neuro-microglia changes in the brain and in cells as well, under lipotoxic stress. Nec-1S reduced tau, and amyloid oligomer load. Moreover, Nec-1S restored mitochondrial function and autophago-lysosome clearance. The findings highlight the central impact of metabolic syndrome and how Nes-1S, by acting as a multifaceted agent, improved central functioning.

Fingolimod Alleviates Cognitive Deficit in Type 2 Diabetes by Promoting Microglial M2 Polarization via the pSTAT3-jmjd3 Axis.

Sphingosine receptors (S1PRs) are implicated in the progression of neurodegenerative diseases and metabolic disorders like obesity and type 2 diabetes (T2D). The link between S1PRs and cognition in type 2 diabetes, as well as the mechanisms that underpin it, are yet unknown. Neuroinflammation is the common pathology shared among T2D and cognitive impairment. However, the interplay between the M1 and M2 polarization state of microglia, a primary driver of neuroinflammation, could be the driving factor for impaired learning and memory in diabetes. In the present study, we investigated the effects of fingolimod (S1PR1 modulator) on cognition in high-fat diet and streptozotocin-induced diabetic mice. We further assessed the potential pathways linking microglial polarization and cognition in T2D. Fingolimod (0.5 mg/kg and 1 mg/kg) improved M2 polarization and synaptic plasticity while ameliorating cognitive decline and neuroinflammation. Sphingolipid dysregulation was mimicked in vitro using palmitate in BV2 cells, followed by conditioned media exposure to Neuro2A cells. Mechanistically, type 2 diabetes induced microglial activation, priming microglia towards the M1 phenotype. In the hippocampus and cortex of type 2 diabetic mice, there was a substantial drop in pSTAT3, which was reversed by fingolimod. This protective effect of fingolimod on microglial M2 polarization was primarily suppressed by selective jmjd3 blockade in vitro using GSK-J4, revealing that jmjd3 was involved downstream of STAT3 in the fingolimod-enabled shift of microglia from M1 to M2 polarization state. This study suggested that fingolimod might effectively improve cognition in type 2 diabetes by promoting M2 polarization.

Neuroepigenetic Changes in DNA Methylation Affecting Diabetes-Induced Cognitive Impairment.

Chronic diabetic conditions have been associated with certain cerebral complications, that include neurobehavioral dysfunctional patterns and morphological alterations of neurons, especially the hippocampus. Neuroanatomical studies done by the authors have shown decreased total dendritic length, intersections, dendritic length per branch order and nodes in the CA1 hippocampal region of the diabetic brain as compared to its normal control group, indicating reduced dendritic arborization of the hippocampal CA1 neurons. Epigenetic alterations in the brain are well known to affect age-associated disorders, however its association with the evolving diabetes-induced damage in the brain is still not fully understood. DNA hypermethylation within the neurons, tend to silent the gene expression of several regulatory proteins. The findings in the study have shown an increase in global DNA methylation in palmitic acid-induced lipotoxic Neuro-2a cells as well as within the diabetic mice brain. Inhibiting DNA methylation, restored the levels of HSF1 and certain HSPs, suggesting plausible effect of DNMTs in maintaining the proteostasis and synaptic fidelity. Neuroinflammation, as exhibited by the astrocyte activation (GFAP), were further significantly decreased in the 5-azadeoxycytidine group (DNMT inhibitor). This was further evidenced by decrease in proinflammatory cytokines TNF⍺, IL-6, and mediators iNOS and Phospho-NFkB. Our results suggest that changes in DNA methylation advocate epigenetic dysregulation and its involvement in disrupting the synaptic exactitude in the hippocampus of diabetic mice model, providing an insight into the pathophysiology of diabetes-induced neuroepigenetic changes.

Neuroepigenetic alterations in the prefrontal cortex of type 2 diabetic mice through DNA hypermethylation.

BACKGROUND: DNA methylation changes have known to downregulate several regulatory proteins epigenetically during various neurodegenerative disorders. Our study aims to understand the effect of this global DNA methylation on the cerebral complications of type 2 diabetes mice, and its notable effect on maintaining the synaptic fidelity. METHODS AND RESULTS: Chronic high fat diet and streptozotocin-induced diabetic mice were studied for the neurobehavioral and neuroanatomic parameters pertaining to prefrontal cortex, subsequently elucidating the associated changes in DNA methylation within these diabetic brains. Further, the impact of this epigenetic dysregulation on HSF1, BDNF and PSD95 were studied by assessing the binding affinity and level of % methylation within the promoter site of their respective genes. Our study suggest increased DNMT aberrations within the prefrontal cortex, with increased MeCP2 levels, confirming DNA hypermethylation. This was in accordance with the altered neurobehavioral changes. Further, the hypermethylation was found to participate in gene silencing of HSF1, BDNF and PSD95 proteins, responsible for maintaining the synaptic fidelity. CONCLUSION: Overall, our study concludes the plausible involvement of neuroepigenetic alterations in the prefrontal cortex (PFC) of the type 2 diabetes mice, specifically DNA hypermethylation. PFC plays a central role in modulating cognitive and other executive functions through its connection with several brain regions, and thus therapeutic strategies targeting epigenetic modulations in it, can pave a way in controlling several neurological alterations in the brain.

NLRP3 inflammasomes: A potential target to improve mitochondrial biogenesis in Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative condition for which no approved treatment exists to prevent collective neuronal death. There is ample evidence that mitochondrial dysfunction, reactive oxygen species (ROS), and associated caspase activity underlie the pathology observed. Neurons rely on mitochondrial activity since they have such high energy consumption. Therefore, it is not surprising that mitochondrial alterations favour neuronal degeneration. In particular, mitochondrial dysregulation contributes to PD, based on the observation that mitochondrial toxins can cause parkinsonism in humans and animal models. Also, it is known that inflammatory cytokine-mediated neuroinflammation is the key pathogenic mechanism in neuronal loss. In recent years, the research has focussed on mitochondria being the platform for nucleotide-binding oligomerization domain-like receptors 3 (NLRP3) inflammasome activation. Mitochondrial dysfunction and NLRP3 activation are emerging as critical players in inducing and sustaining neuroinflammation. Moreover, mitochondrial-derived ROS and mitochondrial DNA (mtDNA) could serve as the priming signal for forming inflammasome complexes responsible for the activation, maturation, and release of pro-inflammatory cytokines, including interleukin-1(IL-1) and interleukin-18 (IL-18). The current review takes a more comprehensive approach to elucidating the link between mitochondrial dysfunction and aberrant NLRP3 activation in PD. In addition, we focus on some inhibitors of NLRP3 inflammatory pathways to alleviate the progression of PD.

Metabolic Regulation of Glia and Their Neuroinflammatory Role in Alzheimer's Disease.

Alzheimer's disease (AD) is an aging-related neurodegenerative disorder. It is characterized clinically by progressive memory loss and impaired cognitive function. Its progression occurs from neuronal synapse loss to amyloid pathology and Tau deposit which eventually leads to the compromised neuronal function. Neurons in central nervous tissue work in a composite and intricate network with the glia and vascular cells. Microglia and astrocytes are becoming the prime focus due to their involvement in various aspects of neurophysiology, such as trophic support to neurons, synaptic modulation, and brain surveillance. AD is also often considered as the sequela of prolonged metabolic dyshomeostasis. The neuron and glia have different metabolic profiles as cytosolic glycolysis and mitochondrial-dependent oxidative phosphorylation (OXPHOS), especially under dyshomeostasis or with aging pertaining to their unique genetic built-up. Various efforts are being put in to decipher the role of mitochondrial dynamics regarding their trafficking, fission/fusion imbalance, and mitophagy spanning over both neurons and glia to improve aging-related brain health. The mitochondrial dysfunction may lead to activation in various signaling mechanisms causing metabolic reprogramming in glia cells, further accelerating AD-related pathogenic events. The glycolytic-dominant astrocytes switch to the neurotoxic phenotype, i.e., disease-associated astrocyte under metabolic stress. The microglia also transform from resting to reactive phenotype, i.e., disease-associated microglia. It may also exist in otherwise a misconception an M1, glycolytic, or M2, an OXPHOS-dependent phenotype. Further, glial transformation plays a vital role in regulating hallmarks of AD pathologies like synapse maintenance, amyloid, and Tau clearance. In this updated review, we have tried to emphasize the metabolic regulation of glial reactivity, mitochondrial quality control mechanisms, and their neuroinflammatory response in Alzheimer's progression.

Glia: A major player in glutamate-GABA dysregulation-mediated neurodegeneration.

The imbalance between glutamate and γ-aminobutyric acid (GABA) results in the loss of synaptic strength leading to neurodegeneration. The dogma on the field considered neurons as the main players in this excitation-inhibition (E/I) balance. However, current strategies focusing only on neurons have failed to completely understand this condition, bringing up the importance of glia as an alternative modulator for neuroinflammation as glia alter the activity of neurons and is a source of both neurotrophic and neurotoxic factors. This review's primary goal is to illustrate the role of glia over E/I balance in the central nervous system and its interaction with neurons. Rather than focusing only on the neuronal targets, we take a deeper look at glial receptors and proteins that could also be explored as drug targets, as they are early responders to neurotoxic insults. This review summarizes the neuron-glia interaction concerning GABA and glutamate, possible targets, and its involvement in the E/I imbalance in neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis.

The Protective Effects of AT2R Agonist, CGP42112A, Against Angiotensin II-Induced Oxidative Stress and Inflammatory Response in Astrocytes: Role of AT2R/PP2A/NFκB/ROS Signaling.

Angiotensin II receptor type 2 (AT2R) agonists have been known to promote neuroprotection by limiting ischemic insult, neuronal proliferation, and differentiation. Further, AT2R agonists have also been associated with the suppression of neuroinflammation and neurodegeneration. Of note, brain astrocytes play a critical role in these neuroinflammatory and neurodegenerative processes. However, the role of AT2R in astrocytic activation remains elusive. Therefore, this study evaluated the role and molecular mechanism of AT2R agonist CGP42112A (CGP) against Angiotensin II (Ang II)-induced astrocytic activation in primary astrocytes, and in a rat model of hypertension. Here, we demonstrated that AT2R activation by CGP abrogated Ang II-induced astrocytic activation, by mitigating the ROS production, mitochondrial dysfunction, IκB-α degradation, NFκB nuclear translocation, and release of TNF-α in astrocytes. However, AT2R-mediated anti-inflammatory effects were reversed by AT2R antagonist, PD123319 (PD), in both in vitro and in vivo conditions. Mechanistically, AT2R via protein phosphatase-2A (PP2A) abrogated the Ang II-induced NFκB activation, ROS generation, and subsequent astrocytic activation. Importantly, PP2A antagonist, okadaic acid, reversed the anti-inflammatory effects of AT2R in Ang II-stimulated primary astrocytes and in the cortex of hypertensive rats. Thus, the present study suggests that AT2R by activating PP2A inhibits oxidative stress and NFκB activation, thereby preventing the astrocytic pro-inflammatory activation. Therefore, AT2R might be advantageous therapeutic target for neuroinflammatory/neurodegenerative diseases perpetuated by astrocytic activation.

Mitochondrial remodelling-a vicious cycle in diabetic complications.

Diabetes mellitus (DM) is a chronic, metabolic condition characterized by excessive blood glucose that causes perturbations in physiological functioning of almost all the organs of human body. This devastating metabolic disease has its implications in cognitive decline, heart damage, renal, retinal and neuronal complications that severely affects quality of life and associated with decreased life expectancy. Mitochondria possess adaptive mechanisms to meet the cellular energy demand and combat cellular stress. In recent years mitochondrial homeostasis has been point of focus where several mechanisms regulating mitochondrial health and function are evaluated. Mitochondrial dynamics plays crucial role in maintaining healthy mitochondria in cell under physiological as well as stress condition. Mitochondrial dynamics and corresponding regulating mechanisms have been implicated in progression of metabolic disorders including diabetes and its complications. In current review we have discussed about role of mitochondrial dynamics under physiological and pathological conditions. Also, modulation of mitochondrial fission and fusion in diabetic complications are described. The available literature supports mitochondrial remodelling as reliable target for diabetic complications.

Anxiety: An ignored aspect of Parkinson's disease lacking attention.

Parkinson's disease (PD) is a progressive neurodegenerative disease which affects millions of population worldwide. It is characterized by motor symptoms such as excessive tremor, bradykinesia, rigidity, postural instability and non-motor symptoms include neuropsychiatric complications like anxiety, depression, insomnia and cognitive impairment, orthostatic hypotension, sexual dysfunction and gastrointestinal complications. Treatment of anxiety in PD poses extensive challenge to global healthcare which makes it urgent to develop innovative treatment for the better management of the disease. The gold standard treatment by Levodopa provides symptomatic relief and its effect on neuropsychiatric complications like anxiety is elusive. Presence of anxiety worsens the condition and challenges therapeutic management of the PD. The in-depth analysis and understanding the molecular mechanism and pathophysiological pathways associated with the onset of anxiety in PD is essential. The disturbances in serotonergic, adrenergic and GABAergic neurons and hypothalamic pituitary adrenal axis play a significant role in the pathophysiology of anxiety. The drugs like Selective Serotonin Reuptake Inhibitors, tricyclic antidepressants and benzodiazepines are useful in the management of anxiety but due to severe side effects and progression of the disease it results in the failure of treatment. The present review imparts an insight in the management of anxiety in PD by understanding molecular mechanism and application of alternative treatment options which can enlighten the perception of researchers towards better therapeutic management of the disease.

AT2R Activation Prevents Microglia Pro-inflammatory Activation in a NOX-Dependent Manner: Inhibition of PKC Activation and p47phox Phosphorylation by PP2A.

Microglia-induced reactive oxygen species (ROS) production and inflammation play an imperative role in neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD). It has been established that angiotensin II type-2 receptor (AT2R) activation is neuroprotective in central nervous system diseases like stroke and AD. However, the involvement of AT2R in NADPH oxidase (NOX)-mediated microglia activation is still elusive. Therefore, the present study investigated the role of AT2R in angiotensin II (Ang II) or Phorbol 12-myristate 13-acetate (PMA)-induced microglia activation in BV2 cells, primary microglia, p47phox knockout (p47KO) microglia, and in vivo. Treatment of microglia with Ang II or PMA induced a significant ROS generation and promoted pro-inflammatory microglia in a NOX-dependent manner. In contrast, AT2R activation by CGP42112A (CGP) inhibited NOX activation, ROS production, and pro-inflammatory microglia activation, while promoting the immunoregulatory microglia. This inhibitory effect of AT2R on NOX and pro-inflammatory activation was attenuated by AT2R antagonist, PD123319. Essentially, NOX inhibition (by DPI) or scavenging cellular ROS (by NAC) or p47KO microglia were immune to Ang II- or PMA-induced pro-inflammatory microglia activation. Mechanistically, AT2R, via activation of protein phosphatase-2A (PP2A), prevented the Ang II- or PMA-induced protein kinase C (PKC) activation and phosphorylation of p47phox, an effect that was reversed by the addition of PP2A inhibitor, Okadaic acid (OA). Importantly, PKC inhibitor, Rottlerin, inhibited the Ang II- or PMA-induced p47phox phosphorylation and ROS generation to the similar extent as AT2R activation. In addition, AT2R activation or p47KO prevented ROS production, pro-inflammatory microglial activation, and sickness behavior in mice model of neuroinflammation. Therefore, the present findings suggested that AT2R, via PP2A-mediated inhibition of PKC, prevents the NOX activation, ROS generation, and subsequent pro-inflammatory activation of microglia.