Department Of Pharmacology
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Item Bacillus Calmette-Gu�rin Vaccine Attenuates Haloperidol-Induced TD-like Behavioral and Neurochemical Alteration in Experimental Rats(2023-11-20T00:00:00) Yedke, Narhari Gangaram; Upadhayay, Shubham; Singh, Randhir; Jamwal, Sumit; Ahmad, Sheikh F.; Kumar, PuneetTardive dyskinesia (TD) is a hyperkinetic movement disorder that displays unusual involuntary movement along with orofacial dysfunction. It is predominantly associated with the long-term use of antipsychotic medications, particularly typical or first-generation antipsychotic drugs such as haloperidol. Oxidative stress, mitochondrial dysfunction, neuroinflammation, and apoptosis are major pathophysiological mechanisms of TD. The BCG vaccine has been reported to suppress inflammation, oxidative stress, and apoptosis and exert neuroprotection via several mechanisms. Our study aimed to confirm the neuroprotective effect of the BCG vaccine against haloperidol-induced TD-like symptoms in rats. The rats were given haloperidol (1 mg/kg, i.p.) for 21 days after 1 h single administration of the BCG vaccine (2 � 107 cfu). Various behavioral parameters for orofacial dyskinesia and locomotor activity were assessed on the 14th and 21st days after haloperidol injection. On the 22nd day, all rats were euthanized, and the striatum was isolated to estimate the biochemical, apoptotic, inflammatory, and neurotransmitter levels. The administration of the BCG vaccine reversed orofacial dyskinesia and improved motor function in regard to haloperidol-induced TD-like symptoms in rats. The BCG vaccine also enhanced the levels of antioxidant enzymes (SOD, GSH) and reduced prooxidants (MDA, nitrite) and pro-apoptotic markers (Cas-3, Cas-6, Cas-9) in rat brains. Besides this, BCG treatment also restored the neurotransmitter (DA, NE, 5-HT) levels and decreased the levels of HVA in the striatum. The study findings suggest that the BCG vaccine has antioxidant, antiapoptotic, and neuromodulatory properties that could be relevant in the management of TD.Item Calcium channelopathies in neurodegenerative disorder: an untold story of RyR and SERCA(Taylor and Francis Ltd., 2023-11-16T00:00:00) Dhureja, Maanvi; Arthur, Richmond; Soni, Divya; Upadhayay, Shubham; Temgire, Pooja; Kumar, PuneetIntroduction: Recent neuroscience breakthroughs have shed light on the sophisticated relationship between calcium channelopathies and movement disorders, exposing a previously undiscovered tale focusing on the Ryanodine Receptor (RyR) and the Sarco/Endoplasmic Reticulum Calcium ATPase (SERCA). Calcium signaling mainly orchestrates neural communication, which regulates synaptic transmission and total network activity. It has been determined that RyR play a significant role in managing neuronal functions, most notably in releasing intracellular calcium from the endoplasmic reticulum. Areas covered: It highlights the involvement of calcium channels such as RyR and SERCA in physiological and pathophysiological conditions. Expert opinion: Links between RyR and SERCA activity dysregulation, aberrant calcium levels, motor and cognitive dysfunction have brought attention to the importance of RyR and SERCA modulation in neurodegenerative disorders. Understanding the obscure function of these proteins will open up new therapeutic possibilities to address the underlying causes of neurodegenerative diseases. The unreported RyR and SERCA narrative broadens the understanding of calcium channelopathies in movement disorders and calls for more research into cutting-edge therapeutic approaches. � 2023 Informa UK Limited, trading as Taylor & Francis Group.Item Therapeutic targeting of angiopoietins in tumor angiogenesis and cancer development(Elsevier B.V., 2023-10-21T00:00:00) Thapa, Komal; Khan, Heena; Kaur, Gagandeep; Kumar, Puneet; Singh, Thakur GurjeetThe formation and progression of tumors in humans are linked to the abnormal development of new blood vessels known as neo-angiogenesis. Angiogenesis is a broad word that encompasses endothelial cell migration, proliferation, tube formation, and intussusception, as well as peri-EC recruitment and extracellular matrix formation. Tumor angiogenesis is regulated by angiogenic factors, out of which some of the most potent angiogenic factors such as vascular endothelial growth factor and Angiopoietins (ANGs) in the body are produced by macrophages and other immune cells within the tumor microenvironment. ANGs have a distinct function in tumor angiogenesis and behavior. ANG1, ANG 2, ANG 3, and ANG 4 are the family members of ANG out of which ANG2 has been extensively investigated owing to its unique role in modifying angiogenesis and its tight association with tumor progression, growth, and invasion/metastasis, which makes it an excellent candidate for therapeutic intervention in human malignancies. ANG modulators have demonstrated encouraging outcomes in the treatment of tumor development, either alone or in conjunction with VEGF inhibitors. Future development of more ANG modulators targeting other ANGs is needed. The implication of ANG1, ANG3, and ANG4 as probable therapeutic targets for anti-angiogenesis treatment in tumor development should be also evaluated. The article has described the role of ANG in tumor angiogenesis as well as tumor growth and the treatment strategies modulating ANGs in tumor angiogenesis as demonstrated in clinical studies. The pharmacological modulation of ANGs and ANG-regulated pathways that are responsible for tumor angiogenesis and cancer development should be evaluated for the development of future molecular therapies. � 2023 Elsevier Inc.Item Impact of noscapine on halting the progression of pentylenetetrazole induced kindling epilepsy in mice(John Wiley and Sons Inc, 2023-09-19T00:00:00) Gupta, Rishav; Soni, Divya; Upadhayay, Shubham; Dhureja, Maanvi; Kumar, PuneetEpilepsy is caused by an excessive recurrent excitatory neuronal firing, characterized by motor, psychomotor, and sensory impairments. Current therapies fail to produce 100% outcomes because of the complexity of the disease, poor diagnosis, and upsurge�to drug-resistant epilepsy. The study repurposed�the drug �noscapine��mainly known for its anti-tussive properties. For the management of epilepsy and its associated secondary complications. To confirm the effect of noscapine, adult mice were injected with pentylenetetrazole (PTZ) (35 mg/kg i.p.) on an alternate day for 29 days to induce epilepsy. Animals were pretreated with noscapine in three doses (5, 10, and 20 mg/kg i.p.) for 33 days. Various behavioural assessments like the open field test, Morris water maze, and tail suspension test were performed to observe animals' locomotor activity, spatial memory, and anxiety-depressive behaviour. On the 34th day, animals were sacrificed, and brains were removed for biochemical estimations. Prolonged PTZ treatment reduced locomotor, learning activity, and increased anxiety-depressive behaviour, which was further confirmed by reduced antioxidant levels such as reduced glutathione (GSH), superoxide dismutase (SOD), and catalase because of increased oxido-nitrosative stress, that is, malondialdehyde (MDA) and nitrite in the brain. In comparison, noscapine pretreatment attenuated PTZ-induced behavioural and biochemical changes in the animals. The results indicate that noscapine ameliorates the oxido-nitrosative stress. However, studies indicate that oxido-nitrosative stress is a significant concern for the GABAergic neurons and promotes the disease progression. Further studies are required to explore the molecular mechanism of noscapine, which might be a practical approach as a newer antiepileptic agent. � 2023 John Wiley & Sons Australia, Ltd.Item Neurodegenerative diseases and brain delivery of therapeutics: Bridging the gap using dendrimers(Editions de Sante, 2023-08-26T00:00:00) Kaur, Amandeep; Singh, Navneet; Kaur, Harmanpreet; Kakoty, Violina; Sharma, Deep Shikha; Khursheed, Rubiya; Babu, Molakpogu Ravindra; Harish, Vancha; Gupta, Gaurav; Gulati, Monica; Kumar, Puneet; Dureja, Harish; Alharthi, Nahed S.; Khan, Farhan R.; Rehman, Zia ur; Hakami, Mohammed Ageeli; Patel, Mrunali; Patel, Rashmin; Zandi, Milad; Vishwas, Sukriti; Dua, Kamal; Singh, Sachin KumarNeurodegenerative diseases (NDs) continue to burden human lives and economic conditions. They continue to challenge the healthcare system due to the associated physiological barriers. Traditional treatment approaches are associated with symptomatic relief and are ineffective in the long run. Dendrimers stand out amongst other nanocarriers due to ease of surface modifications, internal encapsulation, and nanoscale uniformity of the molecule. Moreover, their internal core can encapsulate drug through electrostatic interactions. These are stable carriers in the nanometer size range. These either act as therapeutic agents per se or deliver the target drug across the blood-brain barrier while minimizing toxicity. Emerging as a promising non-invasive approach, they demonstrate the capability to interfere with in-vivo protein aggregation, typically associated with neurodegeneration. They assist via exerting various neuroprotective roles, such as in oxidative stress, neuroinflammation, inhibiting certain biochemical parameters, altering protein misfolding and aggregation, etc. However, certain limitations are associated with their elimination and cytotoxicity. The investigation revealed the masking of exposed cationic surfaces of dendrimers with inert substances, such as polyethylene glycol to limit their cytotoxicity. This review describes the incidences and pathophysiology of several NDs, properties, and methods of dendrimer synthesis, followed by various research to explore dendrimers potential to treat NDs. � 2023 Elsevier B.V.Item Understanding the neuronal synapse and challenges associated with the mitochondrial dysfunction in mild cognitive impairment and Alzheimer's disease(Elsevier B.V., 2023-09-13T00:00:00) Verma, Harkomal; Gangwar, Prabhakar; Yadav, Anuradha; Yadav, Bharti; Rao, Rashmi; Kaur, Sharanjot; Kumar, Puneet; Dhiman, Monisha; Taglialatela, Giulio; Mantha, Anil KumarSynaptic mitochondria are crucial for maintaining synaptic activity due to their high energy requirements, substantial calcium (Ca2+) fluctuation, and neurotransmitter release at the synapse. To provide a continuous energy supply, neurons use special mechanisms to transport and distribute healthy mitochondria to the synapse while eliminating the damaged mitochondria from the synapse. Along the neuron, mitochondrial membrane potential (?) gradient exists and is highest in the somal region. Lower ? in the synaptic region renders mitochondria more vulnerable to oxidative stress-mediated damage. Secondly, mitochondria become susceptible to the release of cytochrome c, and mitochondrial DNA (mtDNA) is not shielded from the reactive oxygen species (ROS) by the histone proteins (unlike nuclear DNA), leading to activation of caspases and pronounced oxidative DNA base damage, which ultimately causes synaptic loss. Both synaptic mitochondrial dysfunction and synaptic failure are crucial factors responsible for Alzheimer's disease (AD). Furthermore, amyloid beta (A?) and hyper-phosphorylated Tau, the two leading players of AD, exaggerate the disease-like pathological conditions by reducing the mitochondrial trafficking, blocking the bi-directional transport at the synapse, enhancing the mitochondrial fission via activating the mitochondrial fission proteins, enhancing the swelling of mitochondria by increasing the influx of water through mitochondrial permeability transition pore (mPTP) opening, as well as reduced ATP production by blocking the activity of complex I and complex IV. Mild cognitive impairment (MCI) is also associated with decline in cognitive ability caused by synaptic degradation. This review summarizes the challenges associated with the synaptic mitochondrial dysfunction linked to AD and MCI and the role of phytochemicals in restoring the synaptic activity and rendering neuroprotection in AD. � 2023 Elsevier B.V. and Mitochondria Research Society. All rights reserved.Item Treatment of diabetic complications: do flavonoids holds the keys?(Taylor and Francis Ltd., 2023-07-12T00:00:00) Chalotra, Rishabh; Gupta, Tanya; Chib, Shivani; Amanat, Muhammed; Kumar, Puneet; Singh, RandhirDiabetes mellitus (DM) is an endocrinological disorder in which blood sugar levels get elevated and if unmanaged, it leads to several critical complications. Existing therapies or drugs are not able to attain absolute control of DM. Moreover, associated side/adverse effects associated with pharmacotherapy further worsen the Quality of life of patients. Present review is focused on therapeutical potential of flavonoids in management of diabetes and diabetic complications. Plenteous literature has established significant potential of flavonoids in the treatment of diabetes and diabetic complications. A number of flavonoids are found to be effective in treatment of not only diabetes but progression of diabetic complication was also found to be attenuated with the use of flavonoids. Moreover, SAR studies of some flavonoids also indicated the that efficacy of flavonoids is increased with a change in functional group of flavonoids in the treatment of diabetes and diabetic complications. A number of clinical trials are into action to investigate the therapeutic potential of flavonoids as first-line drugs or as adjuvants for treatment of diabetes and diabetic complications. Owing to their diverse mechanism of action, efficacy and safety, flavonoids may be conscripted as potential candidate for treatment of diabetic complications. � 2023 Taylor & Francis Group, LLC.Item Bacillus calmette gaurine vaccine ameliorates the neurotoxicity of quinolinic acid in rats via the modulation of antioxidant, inflammatory and apoptotic markers(Elsevier B.V., 2023-05-11T00:00:00) Yedke, Narhari Gangaram; Arthur, Richmond; Kumar, PuneetA mutation in the Huntingtin gene causes �Huntington's disease, which presents as a motor and behavioral impairment. Due to the limited drug therapy for this disease, scientists are constantly searching for newer and alternative drugs that may either retard or prevent the progress of the disease. This study aims to explore the neuroprotective potential of Bacillus Calmette Gaurine (BCG) vaccine against quinolinic acid-induced (QA) neurotoxicity in rats. QA (200 nmol/2 �l, i.s) was injected bilaterally into the rat striatum, after which a single dose of BCG (2 � 10^7, cfu) was given to the rats. Animals were assessed for behavioral parameters on the 14th and 21st days. On the 22nd day, animals were sacrificed, brains were harvested, and striatum was separated to evaluate biochemical, inflammatory, and apoptotic mediators. Histopathological studies were performed using Hematoxyline and Eosin staining to assess neuronal morphology. BCG treatment reversed motor abnormalities, reduced oxidative stress and neuroinflammatory markers, apoptotic mediators and striatal lesions induced by QA treatment. In conclusion, treat' 'ing rats with BCG vaccine (2 � 10^7, cfu) mitigated the quinolinic acid-induced Huntington's disease-like symptoms. Hence, BCG vaccine (2 �10^7, cfu) could be used as an adjuvant in managing HD. � 2023 Elsevier B.V.Item Animal models of Huntington�s disease and their applicability to novel drug discovery and development(Taylor and Francis Ltd., 2023-04-12T00:00:00) Upadhayay, Shubham; Jamwal, Sumit; Kumar, PuneetIntroduction: Huntington�s disease (HD) is a progressive neurodegenerative disorder caused by an expansion in the CAG trinucleotide repeat in huntingtin (Htt) gene. The discovery of the HD-causing gene prompted the creation of new HD animal models, proving that mutations in the HD gene are linked to either loss of function of the wild-type (un-mutated) gene or toxic gain in the function of a mutated gene. Areas Covered: Animal models of HD have led to an increased understanding of its pathogenesis and resulted in the discovery of new therapeutic targets/drugs. The focus of this review is on the selection and validation of animal models for HD drug discovery. Furthermore, several drugs tested using various models in the preclinical phase have been compiled to demonstrate the applicability of these HD animal models. Expert opinion: The applicability of animal models for HD drug discovery has been well demonstrated. Nevertheless, despite the enormous progression made to date, the development of drug therapy to completely alleviate disease progression has not been achieved. Most of the pre-clinically tested drugs have shown promising results in alleviating HD-associated neurodegeneration and motor and non-motor symptoms, but only a few of them thrived to produce satisfactory results in the clinical phase. This failure has raised concerns about the selection of HD animal models and species, and new strategies for selection are mandated. � 2023 Informa UK Limited, trading as Taylor & Francis Group.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.