High-Resolution Respirometry for Mitochondrial Function in Rodent Brain.

High-resolution mitochondrial respirometry is a modern technique that enables to measure mitochondrial respiration in various cell types. It contains chambers with oxygen sensors that measure oxygen concentration via polarography and calculate its consumption. The chamber contains plastic stoppers with injection ports that allow the injection of samples and different substrates, inhibitors, and uncoupler substances to measure mitochondrial respiration with high efficiency. These substances act on the mitochondrial electron transport chain (ETC) and help to assess the mitochondrial ATP production capacity and oxidative phosphorylation. The respirograph obtained with the help of software represents the oxygen consumption in each stage after adding different reagents.

Hypoxia and its effect on the cellular system.

Eukaryotic cells utilize oxygen for different functions of cell organelles owing to cellular survival. A balanced oxygen homeostasis is an essential requirement to maintain the regulation of normal cellular systems. Any changes in the oxygen level are stressful and can alter the expression of different homeostasis regulatory genes and proteins. Lack of oxygen or hypoxia results in oxidative stress and formation of hypoxia inducible factors (HIF) and reactive oxygen species (ROS). Substantial cellular damages due to hypoxia have been reported to play a major role in various pathological conditions. There are different studies which demonstrated that the functions of cellular system are disrupted by hypoxia. Currently, study on cellular effects following hypoxia is an important field of research as it not only helps to decipher different signaling pathway modulation, but also helps to explore novel therapeutic strategies. On the basis of the beneficial effect of hypoxia preconditioning of cellular organelles, many therapeutic investigations are ongoing as a promising disease management strategy in near future. Hence, the present review discusses about the effects of hypoxia on different cellular organelles, mechanisms and their involvement in the progression of different diseases.

Isolation, identification, and molecular characterization of potential keratinolytic fungus sp. from Southern Assam: relevance to poultry wastes and its biological management.

Feather waste is a highly prevalent form of keratinous waste that is generated by the poultry industry. The global daily production of feather waste has been shown to approach 5 million tons, typically being disposed of through methods such as dumping, landfilling, or incineration which contribute significantly to environmental pollutions. The proper management of these keratinous wastes is crucial to avoid environmental contamination. The study was carried out to isolate the keratinolytic fungi from the poultry disposal sites of different region of North-East India to evaluate its potential in bioremediation of the feathers wastes. Out of 12 fungal strains isolated from the sites, the fungus showing the highest zone of hydrolysis on both the skim milk and keratin agar medium was selected for the study and the molecular identification of the isolate was performed through DNA sequence analysis by amplifying the internal transcribed spacer (ITS) region. The sequence results showed higher similarity (above 95%) with Aspergillus spp. and was named Aspergillus sp. Iro-1. The strain was further analyzed for its feather degrading potential which was performed in submerged conditions under optimized conditions. The study showed that the strain could effectively degrade the feathers validated through weight loss method, and the structural deformations in the feathers were visualized through scanning electron microscopy (SEM). Aspergillus sp. Iro-1 was obtained from the southern region of Assam. It would be of great importance as the implementation of this sp. can help in the bioremediation of feathers wastes in this region. This is the first study of identification of feather degrading fungus from southern part of Assam (Barak).

Therapeutic considerations of bioactive compounds in Alzheimer's disease and Parkinson's disease: Dissecting the molecular pathways.

Leading neurodegenerative diseases Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by the impairment of memory and motor functions, respectively. Despite several breakthroughs, there exists a lack of disease-modifying treatment strategies for these diseases, as the available drugs provide symptomatic relief and bring along side effects. Bioactive compounds are reported to bear neuroprotective properties with minimal toxicity, however, a detailed elucidation of their modes of neuroprotection is lacking. The review elucidates the neuroprotective mechanism(s) of some of the major phyto-compounds in pre-clinical and clinical studies of AD and PD to understand their potential in combating these diseases. Curcumin, eugenol, resveratrol, baicalein, sesamol and so on have proved efficient in countering the pathological hallmarks of AD and PD. Curcumin, resveratrol, caffeine and so on have reached the clinical phases of these diseases, while aromadendrin, delphinidin, cyanidin and xanthohumol are yet to be extensively explored in pre-clinical phases. The review highlights the need for extensive investigation of these compounds in the clinical stages of these diseases so as to utilize their disease-modifying abilities in the real field of treatment. Moreover, poor pharmacokinetic properties of natural compounds are constraints to their therapeutic yields and this review suggests a plausible contribution of nanotechnology in overcoming these limitations.

Combating Dopaminergic Neurodegeneration in Parkinson's Disease through Nanovesicle Technology.

Parkinson's disease (PD) is characterized by dopaminergic neurodegeneration, resulting in dopamine depletion and motor behavior deficits. Since the discovery of L-DOPA, it has been the most prescribed drug for symptomatic relief in PD, whose prolonged use, however, causes undesirable motor fluctuations like dyskinesia and dystonia. Further, therapeutics targeting the pathological hallmarks of PD including α-synuclein aggregation, oxidative stress, neuroinflammation, and autophagy impairment have also been developed, yet PD treatment is a largely unmet success. The inception of the nanovesicle-based drug delivery approach over the past few decades brings add-on advantages to the therapeutic strategies for PD treatment in which nanovesicles (basically phospholipid-containing artificial structures) are used to load and deliver drugs to the target site of the body. The present review narrates the characteristic features of nanovesicles including their blood-brain barrier permeability and ability to reach dopaminergic neurons of the brain and finally discusses the current status of this technology in the treatment of PD. From the review, it becomes evident that with the assistance of nanovesicle technology, the therapeutic efficacy of anti-PD pharmaceuticals, phyto-compounds, as well as that of nucleic acids targeting α-synuclein aggregation gained a significant increment. Furthermore, owing to the multiple drug-carrying abilities of nanovesicles, combination therapy targeting multiple pathogenic events of PD has also found success in preclinical studies and will plausibly lead to effective treatment strategies in the near future.

Inosine attenuates post-stroke neuroinflammation by modulating inflammasome mediated microglial activation and polarization.

To date, various agents and molecules have been developed to treat post-stroke neuroinflammation; however, none of them are clinically successful. Post-stroke neuroinflammation is primarily attributed to microglial polarization as the generation of inflammasome complexes shifts microglia to their M1 phenotype and regulates the downstream cascade. Inosine, an adenosine derivative reported to maintain cellular energy homeostasis in stressed conditions. Although the exact mechanism is still unexplored, various studies have reported that it can stimulate axonal sprouting in different neurodegenerative diseases. Hence, our present study aims to decipher the molecular mechanism of inosine mediated neuroprotection by modulating inflammasome signaling towards altered microglial polarization in ischemic stroke. Inosine was administered intraperitoneally to male Sprague Dawley rats at 1 h post-ischemic stroke and was further evaluated for neurodeficit score, motor coordination and long-term neuroprotection. Brains were harvested for infarct size estimation, biochemical assays and molecular studies. Inosine administration at 1 h post ischemic stroke decreased infarct size, neurodeficit score, and improved motor co-ordination. Normalization of biochemical parameters were achieved in the treatment groups. Microglial polarization towards its anti-inflammatory phenotype and modulation of inflammation were evident by relevant gene and protein expression studies. The outcome provides preliminary evidence of inosine mediated alleviation of post-stroke neuroinflammation via modulation of microglial polarization towards its anti-inflammatory form through regulating the inflammasome activation.

Traversing through the cell signaling pathways of neuroprotection by betanin: therapeutic relevance to Alzheimer's Disease and Parkinson's Disease.

Modulation of cell signaling pathways is the key area of research towards the treatment of neurodegenerative disorders. Altered Nrf2-Keap1-ARE (Nuclear factor erythroid-2-related factor 2-Kelch-like ECH-associated protein 1-Antioxidant responsive element) and SIRT1 (Sirtuin 1) cell signaling pathways are considered to play major role in the etiology and pathogenesis of Alzheimer's disease (AD) and Parkinson's disease (PD). Strikingly, betanin, a betanidin 5-O-ß-D-glucoside compound is reported to show commendable anti-oxidative, anti-inflammatory and anti-apoptotic effects in several disease studies including AD and PD. The present review discusses the pre-clinical studies demonstrating the neuroprotective effects of betanin by virtue of its potential to ameliorate oxidative stress, neuroinflammation, abnormal protein aggregation and cell death. It highlights the direct linkage between the neuroprotective abilities of betanin and upregulation of the Nrf2-Keap1-ARE and SIRT1 signaling pathways. The review further hypothesizes the involvement of the betanin-Nrf2-ARE route in the inhibition of beta-amyloid aggregation through beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), one of the pivotal hallmarks of AD. The present review hereby for the first time elaborately discusses the reported neuroprotective abilities of betanin and decodes the Nrf2 and SIRT1 modulating potential of betanin as a primary mechanism of action behind, hence highlighting it as a novel drug candidate for the treatment of neurodegenerative diseases in the near future.

Stem cells alleviate OGD/R mediated stress response in PC12 cells following a co-culture: modulation of the apoptotic cascade through BDNF-TrkB signaling.

Apoptosis mediated by endoplasmic reticulum (ER) stress plays a crucial role in several neurovascular disorders, including ischemia/reperfusion injury (I/R injury). Previous in vitro and in vivo studies have suggested that following I/R injury, ER stress is vital for mediating CCAT-enhancer-binding protein homologous protein (CHOP) and caspase-12-dependent apoptosis. However, its modulation in the presence of stem cells and the underlying mechanism of cytoprotection remains elusive. In vivo studies from our lab have reported that post-stroke endovascular administration of stem cells renders neuroprotection and regulates apoptosis mediated by ER stress. In the current study, a more robust in vitro validation has been undertaken to decipher the mechanism of stem cell-mediated cytoprotection. Results from our study have shown that oxygen-glucose deprivation/reoxygenation (OGD/R) potentiated ER stress and apoptosis in the pheochromocytoma 12 (PC12) cell line as evident by the increase of protein kinase R (PKR)-like ER kinase (p-PERK), p-Eukaryotic initiation factor 2α subunit (EIF2α), activation transcription factor 4 (ATF4), CHOP, and caspase 12 expressions. Following the co-culture of PC12 cells with MSCs, ER stress was significantly reduced, possibly via modulating the brain-derived neurotrophic factor (BDNF) signaling. Furthermore, inhibition of BDNF by inhibitor K252a abolished the protective effects of BDNF secreted by MSCs following OGD/R. Our study suggests that inhibition of ER stress-associated apoptotic pathway with MSCs co-culture following OGD/R may help to alleviate cellular injury and further substantiate the use of stem cells as a therapeutic modality toward neuroprotection following hypoxic injury or stroke in clinical settings.

Cardiolipin-Mediated Alleviation of Mitochondrial Dysfunction Is a Neuroprotective Effect of Statin in Animal Model of Ischemic Stroke.

In clinical settings, the benefit of statin for stroke is debatable as regular statin users may suffer from myalgia, statin-associated myopathy (SAM), and rarely rhabdomyolysis. Studies suggest that patients on statin therapy show lesser vulnerability toward ischemic stroke and post-stroke frailty. Both pre- and post-treatment benefits of statin have been reported as evident by its neuroprotective effects in both cases. As mitochondrial dysfunction following stroke is the fulcrum for neuronal death, we hereby explore the role of statin in alleviating mitochondrial dysfunction by regulating the mitochondrial dynamics. In the present study, we intend to evaluate the role of statin in modulating cardiolipin-mediated mitochondrial functionality and further providing a therapeutic rationale for repurposing statins either as preventive or an adjunctive therapy for stroke.

Advancement in CRISPR/Cas9 Technology to Better Understand and Treat Neurological Disorders.

Neurological disorders have complicated pathophysiology that may involve several genetic mutations. Conventional treatment has limitations as they only treat apparent symptoms. Although, personalized medicine is emerging as a promising neuro-intervention, lack of precision is the major pitfall. Clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system is evolving as a technological platform that may overcome the therapeutic limitations towards precision medicine. In the future, targeting genes in neurological disorders may be the mainstay of modern therapy. The present review on CRISPR/Cas9 and its application in various neurological disorders may provide a platform for its future clinical relevance towards developing precise and personalized medicine.

Endovascular Stem Cell Therapy Promotes Neuronal Remodeling to Enhance Post Stroke Recovery by Alleviating Endoplasmic Reticulum Stress Modulated by BDNF Signaling.

BACKGROUND AND PURPOSE: The impact of increased BDNF expression in brain by endovascular delivered mesenchymal stem cells (MSCs) post stroke towards modulating endoplasmic reticulum (ER) stress mediated neuronal remodeling has not been directly studied. Therefore, the present study investigates ER stress mediated neuronal remodeling following IA MSCs infusion in rodent model of ischemic stroke. METHODS: Ovariectomized Sprague Dawley rats were subjected to MCAO followed by 1 × 105 IA MSCs administration at 6 h. Infarct and functional outcomes at different time points post-stroke were evaluated. Further, various genes and protein expression studies were performed to determine the underlying mechanisms of the effect of IA MSCs towards ER stress mediated neuronal remodeling. RESULTS: Post-stroke IA MSCs administration significantly increased BDNF expression and decreased ER stress markers expression at day 1 post-stroke. A gradual rise in the expression of growth associate protein-43 (GAP 43) and spinophilin were observed at 7, 14- and 28-days post-stroke indicating an increase in neuronal remodeling towards functional restoration. CONCLUSIONS: The results suggest that IA MSCs post-stroke can modulate neuronal remodeling by BDNF-mediated reduction in ER stress that contribute towards functional recovery.

Pharmacological Strategies for Stroke Intervention: Assessment of Pathophysiological Relevance and Clinical Trials.

OBJECTIVES: The present review describes stroke pathophysiology in brief and discusses the spectrum of available treatments with different promising interventions that are in clinical settings or are in clinical trials. METHODS: Relevant articles were searched using Google Scholar, Cochrane Library, and PubMed. Keywords for the search included ischemic stroke, mechanisms, stroke interventions, clinical trials, and stem cell therapy. RESULTS AND CONCLUSION: Stroke accounts to a high burden of mortality and morbidity around the globe. Time is an important factor in treating stroke. Treatment options are limited; however, agents with considerable efficacy and tolerability are being continuously explored. With the advances in stroke interventions, new therapies are being formulated with a hope that these may aid the ongoing protective and reparative processes. Such therapies may have an extended therapeutic time window in hours, days, weeks, or longer and may have the advantage to be accessible by a majority of the patients.

Assessment of Mitochondrial Complex II and III Activity in Brain Sections: A Histoenzymological Technique.

Mitochondrial impairment stands to be a major factor which contributes to the onset and pathogenesis of several neurodegenerative disorders, of which Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD) are among the notable ones. Extensive researches suggest the probable role of mitochondrial complex II and III dysfunction as underlying players in the pathogenesis of AD, PD, and HD. Present scenario of the world in occurrence of neurodegenerative disorders demands more research and development in this field. The development of enzyme histochemistry as an analytical technique has eased the assessment of mitochondrial complex activity at both qualitative and quantitative levels. Based on the principle of redox reactions of chromogenic substrates catalyzed by the enzymes in question, this histochemical analysis has been applied by researchers worldwide and has proved to be reliable. The present chapter hereby discusses the methods followed in performing histoenzymology of mitochondrial complex II and III activity. The chapter also puts light on the precautions which should be followed while performing histoenzymology in order to yield significant results.

Garcinia morella extract confers dopaminergic neuroprotection by mitigating mitochondrial dysfunctions and inflammation in mouse model of Parkinson's disease.

Dopaminergic neuroprotection is the main interest in designing novel therapeutics against Parkinson's disease (PD). In the process of dopaminergic degeneration, mitochondrial dysfunctions and inflammation are significant. While the existing drugs provide symptomatic relief against PD, a therapy conferring total neuroprotection by targeting multiple degenerative pathways is still lacking. Garcinia morella is a common constituent of Ayurvedic medication and has been used for the treatment of inflammatory disorders. The present study investigates whether administration of G. morella fruit extract (GME) in MPTP mouse model of PD protects against dopaminergic neurodegeneration, including the underlying pathophysiologies, and reverses the motor behavioural abnormalities. Administration of GME prevented the loss of dopaminergic cell bodies in the substantia nigra and its terminals in the corpus striatum of PD mice. Subsequently, reversal of parkinsonian behavioural abnormalities, viz. akinesia, catalepsy, and rearing, was observed along with the recovery of striatal dopamine and its metabolites in the experimental model. Furthermore, reduced activity of the mitochondrial complex II in the nigrostriatal pathway of brain of the mice was restored after the administration of GME. Also, MPTP-induced enhanced activation of Glial fibrillary acidic protein (GFAP) and neuronal nitric oxide synthase (nNOS) in the nigrostriatal pathway, which are the markers of inflammatory stress, were found to be ameliorated on GME treatment. Thus, our study presented a novel mode of dopaminergic neuroprotection by G. morella in PD by targeting the mitochondrial dysfunctions and neuroinflammation, which are considered to be intricately associated with the loss of dopaminergic neurons.

Targeting the Pathological Hallmarks of Alzheimer's Disease Through Nanovesicleaided Drug Delivery Approach.

INTRODUCTION: Nanovesicle technology is making a huge contribution to the progress of treatment studies for various diseases, including Alzheimer's disease (AD). AD is the leading neurodegenerative disorder characterized by severe cognitive impairment. Despite the prevalence of several forms of anti-AD drugs, the accelerating pace of AD incidence cannot becurbed, and for rescue, nanovesicle technology has grabbed much attention. METHODOLOGY: Comprehensive literature search was carried out using relevant keywords and online database platforms. The main concepts that have been covered included a complex pathomechanism underlying increased acetylcholinesterase (AchE) activity, ß-amyloid aggregation, and tau-hyperphosphorylation forming neurofibrillary tangles (NFTs) in the brain, which are amongst the major hallmarks of AD pathology. Therapeutic recommendations exist in the form of AchE inhibitors, along with anti-amyloid and anti-tau therapeutics, which are being explored at a high pace. The degree of the therapeutic outcome, however, gets restricted by the pharmacological limitations. Susceptibility to peripheral metabolism and rapid elimination, inefficiency to cross the blood-brain barrier (BBB) and reach the target brain site are the factors that lower the biostability and bioavailability of anti-AD drugs. The nanovesicle technology has emerged as a route to preserve the therapeutic efficiency of the anti-AD drugs and promote AD treatment. The review hereby aims to summarize the developments made by the nanovesicle technology in aiding the delivery of synthetic and plant-based therapeutics targeting the molecular mechanism of AD pathology. CONCLUSION: Nanovesicles appear to efficiently aid in target-specific delivery of anti-AD therapeutics and nullify the drawbacks posed by free drugs, besides reducing the dosage requirement and the adversities associated. In addition, the nanovesicle technology also appears to uplift the therapeutic potential of several phyto-compounds with immense anti-AD properties. Furthermore, the review also sheds light on future perspectives to mend the gaps that prevail in the nanovesicle-mediated drug delivery in AD treatment strategies.

Post-stroke Impairment of the Blood-Brain Barrier and Perifocal Vasogenic Edema Is Alleviated by Endovascular Mesenchymal Stem Cell Administration: Modulation of the PKCδ/MMP9/AQP4-Mediated Pathway.

Post-stroke edema and upregulation of aquaporin 4 (AQP4) water transport channels play a significant role in the progression of stroke pathology and deteriorating stroke outcomes. Prior studies from our lab have demonstrated the safety and efficacy of intra-arterial (IA) 1 × 105 mesenchymal stem cells (MSCs) administration post-stroke towards functional restoration and neuroprotection. Protein kinases have been reported to be involved in the signaling cascade of edema, with evidence supporting both its upregulation and downregulation at 24 h post-stroke. Among different protein kinase C (PKC) isoforms, the δ isoform is widely reported to play a pivotal role in the progression of ischemic reperfusion injury. Our present study aims to decipher the molecular mechanism of post-stroke IA MSCs mediated alleviation of perifocal vasogenic edema by PKCδ-mediated AQP4 regulation. Ovariectomized female SD rats were infused with 1 × 105 IA MSCs at 6 h post middle cerebral artery occlusion (MCAo). Animals were evaluated for behavioral and functional outcomes. Brains were harvested for evaluating infarct size and brain edema. Further, brain tissues were used for biochemical and molecular studies to decipher the possible molecular mechanism related to the regulation of PKCδ-mediated AQP4 expression. 1 × 105 IA MSCs at 6 h post-stroke confers neuroprotection as evident by the reduction in infarct size, edema, and improvement of functional outcome. An increase in GSH and catalase and a reduction in nitrite and MDA were observed along with a decrease in AQP4 and PKCδ expressions within the cortical brain regions of IA MSC-infused animals. The study gives preliminary evidence that IA MSCs administration post-stroke modulates PKCδ to regulate AQP4 expression which alleviates vasogenic edema towards neuroprotection. The study is novel and clinically relevant as no previous studies have looked into this aspect following IA delivery of stem cells in an animal model of ischemic stroke.

Sirtuin-1 - Mediated NF-κB Pathway Modulation to Mitigate Inflammasome Signaling and Cellular Apoptosis is One of the Neuroprotective Effects of Intra-arterial Mesenchymal Stem Cell Therapy Following Ischemic Stroke.

AIM: Stroke results in long term serious disability that affect millions across the globe. Several clinical and preclinical studies have reinforced the therapeutic use of stem cells in stroke patients to enhance their quality of life. Previous studies from our lab have demonstrated that 1*105 allogeneic bone marrow-derived mesenchymal stem cells (BM-MSCs) when given intraarterially (IA) render neuroprotection by modulating the expression of inflammasomes. Sirtuins are a class of important deacylases having a significant role in cellular functioning. Sirtuin-1 (SIRT-1) is an important enzyme essential for regulating cellular metabolism, which is reduced following an ischemic episode. The present study aims to unviel the role of MSCs in regulating the brain SIRT-1 levels following stroke and the involvement of SIRT-1 in regulating inflammasome signaling to reduce cellular apoptosis towards rendering neuroprotection. MATERIALS AND METHODS: 6 h post-reversible middle cerebral artery occlusion (MCAo), ovariectomized Sprague Dawley (SD) rats were infused intraarterially with 1*105 MSCs. 24 h after MCAo animals were examined for functional and behavioral outcomes. Brains were collected for assessing size of infarct and neuronal morphology. Molecular and immunofluroscence studies were also performed for assessing changes in gene and protein expressions. Extent of apoptosis was also determined in different groups. Inhibition study with SIRT-1 specific inhibitor EX-527 was also performed. RESULTS: A reduction in infarct size and improvement in motor functional and behavioral outcomes following infusion of MSCs IA at 6 h post-stroke was observed. Increase in average neuronal density and neuronal length was also seen. Increased expression of SIRT-1, BDNF and concomitant reduction in the expression of different inflammatory and apoptotic markers in the brain cortical regions were observed following MSCs treatment. CONCLUSION: Our study provides a preliminary evidence that post-stroke IA MSCs therapy regulates SIRT-1 to modulate NF-κB pathway to mitigate inflammasome signaling and cellular apoptosis. This study using IA approach for administering MSCs is highly relevant clinically. Our study is the first to report that neuroprotective effects of IA MSCs in rodent focal ischemia is mediated by SIRT-1 regulation of inflammasome signaling.

Garcinol blocks motor behavioural deficits by providing dopaminergic neuroprotection in MPTP mouse model of Parkinson's disease: involvement of anti-inflammatory response.

Although the etiology of Parkinson's disease (PD) is poorly understood, studies in animal models revealed loss of dopamine and the dopaminergic neurons harbouring the neurotransmitter to be the principal cause behind this neuro-motor disorder. Neuroinflammation with glial cell activation is suggested to play a significant role in dopaminergic neurodegeneration. Several biomolecules have been reported to confer dopaminergic neuroprotection in different animal models of PD, owing to their anti-inflammatory potentials. Garcinol is a tri-isoprenylated benzophenone isolated from Garcinia sp. and accumulating evidences suggest that this molecule could provide neuroprotection by modulating oxidative stress and inflammation. However, direct evidence of dopaminergic neuroprotection by garcinol in the pre-clinical model of PD is not yet reported. The present study aims to investigate whether administration of garcinol in the MPTP mouse model of PD may ameliorate the cardinal motor behavioural deficits and prevent the loss of dopaminergic neurons. As expected, garcinol blocked the parkinsonian motor behavioural deficits which include akinesia, catalepsy, and rearing anomalies in the mice model. Most importantly, the degeneration of dopaminergic cell bodies in the substantia nigra region was significantly prevented by garcinol. Furthermore, garcinol reduced the inflammatory marker, glial fibrillary acidic protein, in the substantia nigra region. Since glial hyperactivation-mediated inflammation is inevitably associated with the loss of dopaminergic neurons, our study suggests the anti-inflammatory role of garcinol in facilitating dopaminergic neuroprotection in PD mice. Hence, in the light of the present study, it is suggested that garcinol is an effective anti-parkinsonian agent to block motor behavioural deficits and dopaminergic neurodegeneration in PD.

Endovascular Stem Cell Therapy Post Stroke Rescues Neurons from Endoplasmic Reticulum Stress-Induced Apoptosis by Modulating Brain-Derived Neurotrophic Factor/Tropomyosin Receptor Kinase B Signaling.

Ischemic stroke is devastating, with serious long-term disabilities affecting millions of people worldwide. Growing evidence has shown that mesenchymal stem cells (MSCs) administration after stroke provides neuroprotection and enhances the quality of life in stroke patients. Previous studies from our lab have shown that 1 × 105 MSCs administered intra-arterially (IA) at 6 h post stroke provide neuroprotection through the modulation of inflammasome and calcineurin signaling. Ischemic stroke induces endoplasmic reticulum (ER) stress, which exacerbates the pathology. The current study intends to understand the involvement of brain-derived neurotrophic factor/tropomyosin receptor kinase B (BDNF/TrkB) signaling in preventing apoptosis induced by ER stress post stroke following IA MSCs administration. Ischemic stroke was induced in ovariectomized female Sprague Dawley rats. The MSCs were administered IA, and animals were sacrificed at 24 h post stroke. Infarct area, neurological deficit score, motor coordination, and biochemical parameters were evaluated. The expression of various genes and proteins was assessed. An inhibition study was also carried out to confirm the involvement of BDNF/TrkB signaling in ER stress-induced apoptosis. IA-administered MSCs improved functional outcomes, reduced infarct area, increased neuronal survival, and normalized biochemical parameters. mRNA and protein expression of ER stress markers were reduced, while those of BDNF and TrkB were increased. Reduction in ER stress-mediated apoptosis was also observed. The present study shows that IA MSCs administration post stroke provides neuroprotection and can modulate ER stress-mediated apoptosis via the BDNF/TrkB signaling pathway.