Department Of Pharmacology
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Item An Overview of the Pathophysiological Mechanisms of 3-Nitropropionic Acid (3-NPA) as a Neurotoxin in a Huntington's Disease Model and Its Relevance to Drug Discovery and Development(Springer, 2023-02-04T00:00:00) Upadhayay, Shubham; Yedke, Narhari Gangaram; Rahi, Vikrant; Singh, Surbhi; Kumar, Sachin; Arora, Anchal; Chandolia, Priyanka; Kaur, Prabhsharan; Kumar, Mandeep; Koshal, Prashant; Jamwal, Sumit; Kumar, PuneetAnimal models are used to better understand the various mechanisms involved in the pathogenesis of diseases and explore potential pathways that will aid in discovering therapeutic targets. 3-Nitropropionic Acid (3-NPA) is a neurotoxin used to induce Huntington's disease (HD)-like symptoms in experimental animals. The 3-NPA is a fungus toxin that impairs the complex II (succinate dehydrogenase) activity of the mitochondria and reduces ATP synthesis, leading to excessive production of free radicals resulting in the degeneration of GABAergic medium spiny neurons (MSNs) in the striatum. This is characterized by motor impairments a key clinical manifestation of HD. 3-NPA has the potential to alter several cellular processes, including mitochondrial functions, oxidative stress, apoptosis, and neuroinflammation mimicking HD-like pathogenic conditions in animals. This review strives to provide a new insight towards the 3-NPA induced molecular dysfunctioning in developing an animal model of HD. Moreover, we summarise several preclinical studies that support the use of the 3-NPA-induced models for drug discovery and development in HD. This review is a collection of various articles that were published from 1977 to 2022 on Pubmed (1639), Web of Science (2139), and Scopus (2681), which are related to the 3-NPA induced animal model. Graphical Abstract: [Figure not available: see fulltext.] � 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.Item Repurposing artemisinins as neuroprotective agents: a focus on the PI3k/Akt signalling pathway(Springer Science and Business Media Deutschland GmbH, 2022-12-05T00:00:00) Arthur, Richmond; Navik, Umashanker; Kumar, PuneetArtemisinin and its derivatives, since their discovery by professor Tu Youyou in the early 1970s, have been the bedrock for the management of malaria globally. Recent works have implied that they could be used to manage other diseases including neurodegenerative disorders. Neurodegenerative disorders mainly occur in the adult population resulting from a progressive deterioration of neuronal structures. These include Parkinson�s disease (PD), Alzheimer�s disease (AD), Huntington�s disease (HD), and Multiple sclerosis (MS), among others. The PI3K/Akt signaling pathway plays a significant role in the central nervous system. It has been investigated extensively for its role in central nervous system physiological processes such as cell survival, autophagy, neuronal proliferation, and synaptic plasticity. Therefore, the modulation of this pathway will be crucial in the management of neurodegenerative disorders. This review seeks to compile most of the research findings on the possible neuroprotective role of artemisinins with special emphasis on their modulatory role on the PI3k/Akt pathway. A literature survey was conducted on PubMed, EBSCO, Web of Science, and EMBASE using the keyword artemisinins, and a total of 10,281 articles were retrieved from 1956 to 2022. Among these, 120 articles were examined using Mesh words like PI3k/Akt, neurodegeneration, and neuroinflammation coupled with boolean operators. Most research revealed that artemisinins could help neurodegenerative disorders by modulating the PI3k/Akt with subsequent inhibition of oxidative stress, neuroinflammation, and apoptosis. This paper illustrates that artemisinins could be repurposed as a neuroprotective agent. � 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.Item Neuroprotective role of apocynin against pentylenetetrazole kindling epilepsy and associated comorbidities in mice by suppression of ROS/RNS(Elsevier B.V., 2021-11-30T00:00:00) Jaiswal, Gagandeep; Kumar, PuneetEpilepsy is a neurological disease that transpires due to the unusual synchronized neuronal discharge within the central nervous system, which drives repetitious unprovoked seizures. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is a complex enzyme accountable for reactive oxygen species (ROS) production, neurodegeneration, neurotoxicity, memory impairment, vitiates normal cellular processes, long term potentiation, and thus, implicated in the pathogenesis of epilepsy. Therefore, the present study was sketched to examine the neuroprotective effect of apocynin, NADPH oxidase inhibitor in pentylenetetrazole kindling epilepsy, and induced comorbidities in mice. Mice (either sex) were given pentylenetetrazole (35 mg/kg, i.p.) every other day up to 29 days, and a challenge test was executed on the 33rd day. Pretreatment with apocynin (25, 50, and 100 mg/kg, i.p.) was carried out from 1st to 33rd day. Rotarod and open field test were performed on the 1st, 10th, 20th, and 30th days of the study. Animals were tutored on the morris water maze from 30th to 33rd day, and the retention was registered on the 34th day. Tail suspension test and elevated plus maze were sequentially performed on the 32nd and 33rd day of the study. On the 34th day, animals were sacrificed, and their brains were isolated to conduct biochemical estimation. NADPH oxidase activation due to chronic pentylenetetrazole treatment resulted in generalized tonic-clonic seizures, enhanced oxidative stress, remodeled neurotransmitters' level, and resulted in comorbidities (anxiety, depression, and memory impairment). Pretreatment with apocynin significantly restricted the pentylenetetrazole induced seizure severity, ROS production, neurotransmitter alteration, and comorbid conditions by inhibiting the NADPH oxidase enzyme. � 2021