Browsing by Author "Kaur, Navrattan"

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Ginkgolide B Revamps Neuroprotective Role of Apurinic/Apyrimidinic Endonuclease 1 and Mitochondrial Oxidative Phosphorylation Against Ab 25–35 -Induced Neurotoxicity in Human Neuroblastoma Cells
(Wiley, 2015) Kaur, Navrattan; Dhiman, Monisha; Perez-Polo, J. Regino; Mantha, Anil K.
Accumulating evidence points to roles for oxidative stress, amyloid beta (Aβ), and mitochondrial dysfunction in the pathogenesis of Alzheimer's disease (AD). In neurons, the base excision repair pathway is the predominant DNA repair (BER) pathway for repairing oxidized base lesions. Apurinic/apyrimidinic endonuclease 1 (APE1), a multifunctional enzyme with DNA repair and reduction–oxidation activities, has been shown to enhance neuronal survival after oxidative stress. This study seeks to determine 1) the effect of Aβ25–35 on reactive oxygen species (ROS)/reactive nitrogen species (RNS) levels, 2) the activities of respiratory complexes (I, III, and IV), 3) the role of APE1 by ectopic expression, and 4) the neuromodulatory role of ginkgolide B (GB; from the leaves of Ginkgo biloba). The pro-oxidant Aβ25–35 peptide treatment increased the levels of ROS/RNS in human neuroblastoma IMR-32 and SH-SY5Y cells, which were decreased after pretreatment with GB. Furthermore, the mitochondrial APE1 level was found to be decreased after treatment with Aβ25–35 up to 48 hr, and the level was increased significantly in cells pretreated with GB. The oxidative phosphorylation (OXPHOS; activities of complexes I, III, and IV) indicated that Aβ25–35 treatment decreased activities of complexes I and IV, and pretreatment with GB and ectopic APE1 expression enhanced these activities significantly compared with Aβ25–35 treatment. Our results indicate that ectopic expression of APE1 potentiates neuronal cells to overcome the oxidative damage caused by Aβ25–35. In addition, GB has been shown to modulate the mitochondrial OXPHOS against Aβ25–35-induced oxidative stress and also to regulate the levels of ROS/RNS in the presence of ectopic APE1. This study presents findings from a new point of view to improve therapeutic potential for AD via the synergistic neuroprotective role played by APE1 in combination with the phytochemical GB. © 2015 Wiley Periodicals, Inc.
Indian Herbs and their Therapeutic Potential against Alzheimer’s Disease and other Neurological Disorders
(Wiley, 2017) Kaur, Navrattan; Sarkar, Bibekananda; Gill, Iqbal; Kaur, Sukhchain; Mittal, Sunil; Dhiman, Monisha; Padala, Prasad R.; Perez-Polo, Regino; Mantha, Anil K.
Many present-day diseases are caused by disruption of the delicate balance between the reactive oxygen/nitrogen species (ROS/RNS) produced by oxidants and their scavenging by the antioxidants in the body. Chief among them is Alzheimer's disease (AD), an age-related neurodegenerative disease caused by the accumulation in the brain of amyloid beta (Aβ) plaques and of neurofibrillary tangles made up of the protein tau. Various theories for the pathogenesis of AD have been given, but no precise mechanism of its pathogenesis has been elucidated to date. A number of scientists are currently focusing on developing therapeutics for the prevention and treatment of AD. Natural plant-based products, which have been known traditionally in the treatment of brain disorders, could be a great help. Traditional herbal formulations developed for brain disorders are known as “Medhya drugs” in the Indian system of medicine called “Ayurveda” – a disease-preventive and health-promotive approach dating back to 5000 BC. This review focuses on the traditional use of some common Indian herbs in relation to AD, alongside recent advances in our understanding of their modes of action.
Indian herbs and their therapeutic potential against Alzheimer’s disease: What makes them special? Neuroprotective Effects of Phytochemicals in Neurological Disorders.
(2016) Kaur, Navrattan; Sarkar, Bibekananda; Gill, Iqbal; Kaur, S; Mittal, Sunil; Dhiman, Monisha; Padala, Prasad R; Perez-Polo ,Regino; Mantha, Anil K.
Oxidative Stress Events and Neuronal Dysfunction in Alzheimer’s Disease: Focus on APE1/Ref-1-Mediated Survival Strategies
(Springer, 2014) Kaur, Navrattan; Sarkar, Bibekananda; Mittal, Sunil; Dhiman, Monisha; Taglialatela, Gulio; Perez-polo, Regino J.; Mantha, Anil K.
Alzheimer’s disease (AD) is an important public health problem which affects millions of people worldwide. The major pathological hallmarks associated with AD are the accumulation of amyloid beta (Aβ) in senile plaques and neurofibrillary tangles (NFT) made up of hyperphosphorylated tau proteins. New findings suggest that oligomeric Aβ is a more toxic species than fibrillar Aβ relevant to AD pathology. Although the molecular mechanism(s) underlying the disease is not identified completely, various factors have been implicated in the development of AD. Accumulating evidences point towards the role of oxidative stress and mitochondrial dysfunction in the pathogenesis of AD and recognise them as an early event in AD development. Ageing is considered the greatest risk factor for AD and is linked to oxidative stress which causes accumulation of somatic mutations in mitochondrial DNA (mtDNA) over time and leads to genome instability and mitochondrial dysfunction. Recent studies on AD patients and transgenic mouse models suggest that amyloid precursor protein (APP) and Aβ localise to mitochondria, interact with mitochondrial proteins, disrupt electron transport chain (ETC), increases reactive oxygen species (ROS) level, impair axonal mitochondrial trafficking, thus leading to synaptic damage and cognitive decline associated with AD. It is not known whether accumulation of Aβ is the cause or outcome of declining mitochondrial function in AD. In order to counteract oxidative stress and maintain genome integrity, various DNA repair pathways exist, base excision repair (BER) pathway being the predominant pathway for repairing oxidised base lesions in neuronal cells. APE1 is the central enzyme of the BER pathway, having both repair and redox activities and shown to enhance neuronal survival after oxidative stress. Newer studies are revealing the role of APE1 in maintenance of mitochondrial genome repair and function. In this scenario, antioxidant-based therapy, which could reduce oxidative stress and modulate the activities of APE1, can serve as effective treatment providing neuroprotection in AD. This book chapter summarises some recent developments in understanding the pathogenesis of AD linking Aβ-induced oxidative stress, mitochondrial dysfunction, role of APE1 and phytochemicals toward AD therapeutics.
Phytochemical Ginkgolide B Attenuates Amyloid-␤ 1 - 42 Induced Oxidative Damage and Altered Cellular Responses in Human Neuroblastoma SH-SY5Y Cells
(IOS Press, 2017) Gill, Iqbal; Kaur, Sukhchain; Kaur, Navrattan; Dhiman, Monisha; Mantha, Anil K.
Oxidative stress is an upsurge in reactive oxygen/nitrogen species (ROS/RNS), which aggravates damage to cellular components viz. lipids, proteins, and nucleic acids resulting in impaired cellular functions and neurological pathologies including Alzheimer's disease (AD). In the present study, we have examined amyloid-β (Aβ)-induced oxidative stress responses, a major cause for AD, in the undifferentiated and differentiated human neuroblastoma SH-SY5Y cells. Aβ1-42-induced oxidative damage was evaluated on lipids by lipid peroxidation; proteins by protein carbonyls; antioxidant status by SOD and GSH enzyme activities; and DNA and RNA damage levels by evaluating the number of AP sites and 8-OHG base damages produced. In addition, the neuro-protective role of the phytochemical ginkgolide B (GB) in countering Aβ1-42-induced oxidative stress was assessed. We report that the differentiated cells are highly vulnerable to Aβ1-42-induced oxidative stress events as exerted by the deposition of Aβ in AD. Results of the current study suggest that the pre-treatment of GB, followed by Aβ1-42 treatment for 24 h, displayed neuro-protective potential, which countered Aβ1-42-induced oxidative stress responses in both undifferentiated and differentiated SH-SY5Y neuronal cells by: 1) hampering production of ROS and RNS; 2) reducing lipid peroxidation; 3) decreasing protein carbonyl content; 4) restoring antioxidant activities of SOD and GSH enzymes; and 5) maintaining genome integrity by reducing the oxidative DNA and RNA base damages. In conclusion, Aβ1-42 induces oxidative damage to the cellular biomolecules, which are associated with AD pathology, and are protected by the pre-treatment of GB against Aβ-toxicity. Taken together, this study advocates for phytochemical-based therapeutic interventions against AD.