Scholarly Publications
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This community showcases the academic contributions of faculty and researchers at Banaras Hindu University (BHU) and provides a year-wise compilation of publications across disciplines. Institutional Repository BHU
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PublicationReview Role of Animal Models in Parkinson's Disease (PD): What Role They Play in Preclinical Translational Research(Bentham Science Publishers, 2024) Rajnish Srivastava; Hagera Dilnashin; Devesh Kapoor; Sai Aparna; Elmira Heidarli; Surya Pratap Singh; Vivek JainBackground: Animal models for drug discovery and development in Parkinson ’s disease have played an important role in the characterization of the pathophysiology of diseases and associated mechanisms of injury, drug target identification, and evaluation of novel therapeutic agents for toxicity/safety, pharmacokinetics, pharmacodynamics, and efficacy. Objective: The review is intended to reform the scope, advantages, and limitations of various Parkinson’s Disease models and their scope in translational research. The lack of a gold standard for PD animal models presents a major challenge in devising a validation system. This review is an attempt to provide a way to adopt the validation approach for PD animal model for research. Methods: Because underlying disease mechanisms are so similar across species, it is possible to extrapolate results from Parkinson's disease studies using animal models. Furthermore, behavioural tests used to access the neurobehavioral test with its limitations were explored for rodents, non-human primates, lower-order animals, and invertebrates. The role of gender selectivity and non-selectivity is the one major concern in PD model validation that is addressed in the review. Results: The rigorous validation has been done on animal models for Parkinson's disease (PD) based on comparisons to the human state. Regarding toxicological and safety investigations in PD, non-animal options must be thoroughly validated. There are both advantages and disadvantages to using animal models of Parkinson's disease as proof-of-concept research. Conclusion: The specific animal model selected for a given drug to be tested and developed depends on the goal of the specific study. © 2024 Bentham Science Publishers.PublicationReview HAT and HDAC: Enzyme with Contradictory Action in Neurodegenerative Diseases(Springer, 2024) Richa Singh; Aaina Singh Rathore; Hagera Dilnashin; Priyanka Kumari Keshri; Nitesh Kumar Gupta; Singh Ankit Satya Prakash; Walia Zahra; Shekhar Singh; Surya Pratap SinghIn view of the increasing risk of neurodegenerative diseases, epigenetics plays a fundamental role in the field of neuroscience. Several modifications have been studied including DNA methylation, histone acetylation, histone phosphorylation, etc. Histone acetylation and deacetylation regulate gene expression, and the regular activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs) provides regulatory stages for gene expression and cell cycle. Imbalanced homeostasis in these enzymes causes a detrimental effect on neurophysiological function. Intriguingly, epigenetic remodelling via histone acetylation in certain brain areas has been found to play a key role in the neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. It has been demonstrated that a number of HATs have a role in crucial brain processes such regulating neuronal plasticity and memory formation. The most recent therapeutic methods involve the use of small molecules known as histone deacetylase (HDAC) inhibitors that antagonize HDAC activity thereby increase acetylation levels in order to prevent the loss of HAT function in neurodegenerative disorders. The target specificity of the HDAC inhibitors now in use raises concerns about their applicability, despite the fact that this strategy has demonstrated promising therapeutic outcomes. The aim of this review is to summarize the cross-linking between histone modification and its regulation in the pathogenesis of neurological disorders. Furthermore, these findings also support the notion of new pharmacotherapies that target particular areas of the brain using histone deacetylase inhibitors. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2024.PublicationArticle Moringa oleifera Modulates MPTP-induced Mitochondrial Dysfunction in Parkinson’s Mouse Model: An in silico and in vivo Analysis(Sage Publications India Pvt. Ltd, 2023) Smriti Singh; Priyanka Kumari Keshri; Vijaya Nath Mishra; Surya Pratap SinghBackground: Parkinson’s disease (PD) is a movement-affecting neurodegenerative condition with an unclear etiology. Recent research suggests targeting poly-(adenosine 5-diphosphate-ribose) polymerase 1 (PARP1) as a potential therapeutic approach for PD treatment. Purpose: The purpose of this study is to assess the effect of an ethanolic extract of Moringa oleifera leaves (MOE) on a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonian mouse model, with a specific focus on investigating its potential to mitigate the effects of α-synuclein toxicity, oxidative stress–induced hyper-activation of PARP1, and mitochondrial dysfunction associated with PD pathology. Additionally, this study also intends to investigate the alterations in neurobehavioral and biochemical parameters associated with PD pathology. Materials and Methods: An in silico docking study was conducted to investigate the phytochemicals found in M. oleifera (MO, drumstick plant) leaves as the potent inhibitors of PARP1. An in vivo (neurobehavioral, biochemical, and western blot) study was conducted to assess the neuroprotective effect of MOE on the MPTP-induced Parkinsonian mouse model. Results: The results of in silico study showed that the phytochemicals found in MO leaves could be a potent inhibitor of PAPR1. The in vivo study results showed that MOE significantly ameliorated MPTP-induced neurobehavioral and biochemical deficits. MPTP-induced mitochondrial enzyme-complex deficits were found to be restored in MOE-treated mice. Additionally, the result obtained in the western blot analysis showed that MOE significantly restored the levels of tyrosine hydroxylase in MPTP-intoxicated mice. MOE enhanced the expression of the anti-apoptotic factor (Bcl-2) and suppressed the expression of pro-apoptotic factors (Bax and caspase-3). Additionally, the enhanced levels of α-synuclein and PARP1 were significantly suppressed by MOE. Conclusion: Our findings suggest that MOE may possess pharmacological properties that inhibit neuronal damage in MPTP-intoxicated mice. Thus, MOE could be used as a therapeutic agent that can protect dopaminergic neurons from PARP1-induced neuronal damage. © The Author(s) 2023.PublicationArticle Curcumin Modulates p62-Keap1-Nrf2-Mediated Autophagy in Rotenone-Induced Parkinson’s Disease Mouse Models(American Chemical Society, 2022) Aaina Singh Rathore; Saumitra Sen Singh; Hareram Birla; Walia Zahra; Priyanka Kumari Keshri; Hagera Dilnashin; Richa Singh; Shekhar Singh; Surya Pratap SinghAutophagy mediates self-digestion of abnormally aggregated proteins and organelles present in the cytoplasm. This mechanism may prove to be neuroprotective against Parkinson’s disease (PD) by clearing misfolded α-synuclein (α-syn) aggregates from dopaminergic neurons. p62, an adaptor protein acts as a selective substrate for autophagy and regulates the formation as well as the degradation of protein aggregates. p62 sequesters keap1 freeing Nrf2 and consequently activating the transcription of its target genes. In the present study, we aimed to investigate the anti-parkinsonian activity of curcumin targeting primarily activation of autophagy via the Nrf2-Keap1 pathway. The mice were subcutaneously injected with rotenone (2.5 mg/kg bodyweight) and co-treated with oral administration of curcumin (80 mg/kg bodyweight) for 35 days. Following completion of dosing, motor activities, anti-oxidative potential, mitochondrial dysfunction, and various protein expressions, including Nrf2, Keap1, p62, LC3, Bcl2, Bax, and caspase 3, were assessed. The results revealed that curcumin restored the motor coordination and anti-oxidative activity while improving the mitochondrial functioning in PD mice. Autophagy was evaluated by the change in the expression of autophagic markers, p62 and LC3-II. Reduced p62 and LC3-II expressions in the rotenone mouse model of PD confirmed the compromised autophagy pathway, consequently increasing the aggregation of misfolded protein α-syn. Whereas, curcumin treatment-enhanced autophagy-mediated clearance of misfolded α-syn proteins by increasing the LC3-II expression and blocked apoptotic cascade. Curcumin administration upregulated the Nrf2 expression and normalized the Nrf2-Keap1 pathway, which justifies the improved anti-oxidative activity. Therefore, the findings reveal that curcumin is a Nrf2-inducer and is endowed with neuroprotective potential, which may prove to be a potential candidate for the anti-Parkinson’s disease treatment therapy. © 2023 American Chemical Society.PublicationReview Neuroprotection by Mucuna pruriens in Neurodegenerative Diseases(Springer, 2022) Walia Zahra; Hareram Birla; Saumitra Sen Singh; Aaina Singh Rathore; Hagera Dilnashin; Richa Singh; Priyanka Kumari Keshri; Priyanka Gautam; Surya Pratap SinghThe medicinal plant Mucuna pruriens (Fabaceae) is widely known for its anti-oxidative and anti-inflammatory properties. It is a well-established drug in Ayurveda and has been widely used for the treatment of neurological disorders and male infertility for ages. The seeds of the plant have potent medicinal value and its extract has been tested in different models of neurodegenerative diseases, especially Parkinson's disease (PD). Apart from PD, Mucuna pruriens is now being studied in models of other nervous systems disorders such as Alzheimer's disease (AD), Amyotrophic lateral sclerosis (ALS) and stroke because of its neuroprotective importance. This review briefly discusses the pathogenesis of PD, AD, ALS and stroke. It aims to summarize the medicinal importance of Mucuna pruriens in treatment of these diseases, and put forward the potential targets where Mucuna pruriens can act for therapeutic interventions. In this review, the effect of Mucuna pruriens on ameliorating the neurodegeneration evident in PD, AD, ALS and stroke is briefly discussed. The potential targets for neuroprotection by the plant are delineated, which can be studied further to validate the hypothesis regarding the use of Mucuna pruriens for the treatment of these diseases. © 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.PublicationReview Epigenetic Modulation in Parkinson’s Disease and Potential Treatment Therapies(Springer, 2021) Aaina Singh Rathore; Hareram Birla; Saumitra Sen Singh; Walia Zahra; Hagera Dilnashin; Richa Singh; Priyanka Kumari Keshri; Surya Pratap SinghIn the recent past, huge emphasis has been given to the epigenetic alterations of the genes responsible for the cause of neurological disorders. Earlier, the scientists believed somatic changes and modifications in the genetic makeup of DNA to be the main cause of the neurodegenerative diseases. With the increase in understanding of the neural network and associated diseases, it was observed that alterations in the gene expression were not always originated by the change in the genetic sequence. For this reason, extensive research has been conducted to understand the role of epigenetics in the pathophysiology of several neurological disorders including Alzheimer’s disease, Parkinson’s disease and, Huntington’s disease. In a healthy person, the epigenetic modifications play a crucial role in maintaining the homeostasis of a cell by either up-regulating or down-regulating the genes. Therefore, improved understanding of these modifications may provide better insight about the diseases and may serve as potential therapeutic targets for their treatment. The present review describes various epigenetic modifications involved in the pathology of Parkinson’s Disease (PD) backed by multiple researches carried out to study the gene expression regulation related to the epigenetic alterations. Additionally, we will briefly go through the current scenario about the various treatment therapies including small molecules and multiple phytochemicals potent enough to reverse these alterations and the future directions for a better management of PD. © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.PublicationArticle Neuroprotection of rotenone-induced parkinsonism by ursolic acid in pd mouse model(Bentham Science Publishers, 2020) Walia Zahra; Sachchida Nand Rai; Hareram Birla; Saumitra Sen Singh; Aaina Singh Rathore; Hagera Dilnashin; Richa Singh; Chetan Keswani; Rakesh K. Singh; Surya Pratap SinghBackground: Parkinson’s Disease (PD) is characterized by both motor and non-motor symptoms. The presynaptic neuronal protein, α-Synuclein, plays a pivotal role in PD pathogenesis and is associated with both genetic and sporadic origin of the disease. Ursolic Acid (UA) is a well-known bioactive compound found in various medicinal plants, widely studied for its anti-inflammatory and antioxidant activities. Objective: In this research article, the neuroprotective potential of UA has been further explored in the Rotenone-induced mouse model of PD. Methods: To investigate our hypothesis, we have divided mice into 4 different groups, control, drug only control, Rotenone-intoxicated group, and Rotenone-intoxicated mice treated with UA. After the completion of dosing, behavioral parameters were estimated. Then mice from each group were sacri-ficed and the brains were isolated. Further, the biochemical tests were assayed to check the balance between the oxidative stress and endogenous anti-oxidants; and TH (Tyrosine Hydroxylase), α-Synuclein, Akt (Serine-threonine protein kinase), ERK (Extracellular signal-regulated kinase) and inflammatory parameters like Nuclear factor-κB (NF-κB) and Tumor Necrosis Factor-α (TNF-α) were assessed using Immunohistochemistry (IHC). Western blotting was also done to check the expressions of TH and α-Synuclein. Moreover, the expression levels of PD related genes like α-Synuclein, β-Synuclein, Interleukin-1β (IL-1β), and Interleukin-10 (IL-10) were assessed by using Real-time PCR. Results: The results obtained in our study suggested that UA significantly reduced the overexpression of α-Synuclein and regulated the phosphorylation of survival-related kinases (Akt and ERK) apart from alleviating the behavioral abnormalities and protecting the dopaminergic neurons from oxidative stress and neuroinflammation. Conclusion: Thus, our study shows the neuroprotective potential of UA, which can further be explored for possible clinical intervention. © 2020 Bentham Science Publishers.PublicationReview NF-κB-Mediated Neuroinflammation in Parkinson’s Disease and Potential Therapeutic Effect of Polyphenols(Springer, 2020) Saumitra Sen Singh; Sachchida Nand Rai; Hareram Birla; Walia Zahra; Aaina Singh Rathore; Surya Pratap SinghDifferent animal and human studies from last two decades in the case of Parkinson’s disease (PD) have concentrated on oxidative stress due to increased inflammation and cytokine-dependent neurotoxicity leading to induction of dopaminergic (DA) degeneration pathway in the nigrostriatal region. Chronic inflammation, the principle hallmark of PD, forms the basis of neurodegeneration. Aging in association with activation of glia due to neuronal injury, perhaps because of immune alterations and genetic predispositions, leads to deregulation of inflammatory pathways premising the onset of PD. A family of inducible transcription factors, nuclear factor-κB (NF-κB), is found to show expression in various cells and tissues, such as microglia, neurons, and astrocytes which play an important role in activation and regulation of inflammatory intermediates during inflammation. Both canonical and non-canonical NF-κB pathways are involved in the regulation of the stimulated cells. During the prodromal/asymptomatic stage of age-associated neurodegenerative diseases (i.e., PD and AD), chronic neuroinflammation may act silently as the driver of neuronal dysfunction. Though research has provided an insight over age-related neurodegeneration in PD, elaborative role of NF-κB in neuroinflammation is yet to be completely understood and thus requires more investigation. Polyphenols, a group of naturally occurring compound in medicinal plants, have gained attention because of their anti-oxidative and anti-neuroinflammatory properties in neurodegenerative diseases. In this aspect, this review highlights the role of NF-κB and the possible therapeutic roles of polyphenols in NF-κB-mediated neuroinflammation in PD. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.PublicationBook Chapter The global economic impact of neurodegenerative diseases: Opportunities and challenges(Springer Singapore, 2019) Walia Zahra; Sachchida Nand Rai; Hareram Birla; Saumitra Sen Singh; Hagera Dilnashin; Aaina Singh Rathore; Surya Pratap SinghThe main challenge in today’s world to the healthcare system is the elevated occurrence of the neurodegenerative disorders. Progress in the field of bioinformatics and biomedical research has allowed us to understand the pathobiology of the neurodegenerative disorders in a detailed manner. The threat of these diseases increases with aging, and Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and Huntington’s disease are the major ones affecting the public health and posing the higher economic burden. The research centers, pharmaceutical companies, and academic institutions are conducting research work in collaborations these days to enhance the development of new therapeutic strategies and develop novel drugs in a sustainable way. This can help in the development of safer therapies with reduced risk and can help in developing the authentic and evident biomarkers so that the disease can be diagnosed at early stages and treated accordingly. The advancement can therefore help in improving the quality of life of patients suffering from these debilitating neurodegenerative disorders and can also help in providing the job opportunities to the students interested in drug development program. © Springer Nature Singapore Pte Ltd. 2020.PublicationArticle Tinospora cordifolia Suppresses Neuroinflammation in Parkinsonian Mouse Model(Humana Press Inc., 2019) Hareram Birla; Sachchida Nand Rai; Saumitra Sen Singh; Walia Zahra; Arun Rawat; Neeraj Tiwari; Rakesh K. Singh; Abhishek Pathak; Surya Pratap SinghParkinson’s disease (PD), a neurodegenerative central nervous system disorder, is characterised by progressive loss of nigrostriatal neurons in basal ganglia. Previous studies regarding PD have suggested the role of oxidative stress along with neuroinflammation in neurodegeneration. Accordingly, our study explore the anti-inflammatory activity of Tinospora cordifolia aqueous extract (TCAE) in 1-methyl-4-phenyl-1,2,3,6-tetra hydropyridine (MPTP)-intoxicated Parkinsonian mouse model. MPTP-intoxicated mice showed significant behavioral and biochemical abnormalities which were effectively reversed by TCAE. It is evident that TCAE inhibits the MPTP-intoxicated Nuclear factor-κB (NF-κB) activation and its associated pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) from immunohistochemistry and Western blot analysis. In MPTP-intoxicated mice, microglial and astroglial-specific inflammatory markers, ionized calcium binding adaptor molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP), respectively were increased while were significantly reduced in TCAE treatment. Expression of pro-inflammatory cytokine genes, TNF-α, Interleukin-12 (IL-12) and Interleukin-1β (IL-1β) were found to be upregulated in MPTP-intoxicated mice, whereas TCAE treatment restored their levels. Additionally, anti-inflammatory factor Interleukin-10 (IL-10) gene was found to be downregulated in MPTP-intoxicated mice which were significantly restored by TCAE treatment. Tyrosine hydroxylase (TH) expression was reduced in MPTP-intoxicated mice, while its expression was significantly increased in TCAE-treated group. Our result strongly suggests that T. cordifolia protects dopaminergic neurons by suppressing neuroinflammation in MPTP-induced Parkinsonian mouse model. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.