Department Of Pharmacology
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Item ?-sitosterol Protects against Aluminium Chloride-mediated Neurotoxicity(Bentham Science Publishers, 2023-03-09T00:00:00) Yadav, Sanjay; Aggarwal, Punita; Khan, Faiz; Khodve, Gopal; Padhy, Dibya Sundar; Yadav, Poonam; Banerjee, SugatoObjective: The objective of this study is to investigate the neuroprotective effects of ?-sitosterol using the AlCl3 model of Alzheimer's Disease. Methods: AlCl3 model was used to study cognition decline and behavioral impairments in C57BL/6 mice. Animals were randomly assigned into 4 groups with the following treatments: Group 1 received normal saline for 21 days, Group 2 received AlCl3 (10 mg/kg) for 14 days; Group 3 received AlCl3(10 mg/kg) for 14 days + ?-sitosterol (25mg/kg) for 21 days; while Group 4 was administered ?-sitosterol (25mg/kg) for 21 days. On day 22, we performed the behavioral studies using a Y maze, passive avoidance test, and novel object recognition test for all groups. Then the mice were sacrificed. The corticohippocampal region of the brain was isolated for acetylcholinesterase (AChE), acetylcholine (ACh), and GSH estimation. We conducted histopathological studies using Congo red staining to measure ?-amyloid deposition in the cortex and hippocampal region for all animal groups. Results: AlCl3 successfully induced cognitive decline in mice following a 14-day induction period, as shown by significantly decreased (p < 0.001) in step-through latency, % alterations, and preference index values. These animals also exhibited a substantial decrease in ACh (p <0.001) and GSH (p < 0.001) and a rise in AChE (p < 0.001) compared to the control group. Mice administered with AlCl3 and ?-sitosterol showed significantly higher step-through latency time, % alteration time, and % preference index (p < 0.001) and higher levels of ACh, GSH, and lower levels of AChE in comparison to the AlCl3 model. AlCl3-administered animals also showed higher ?-amyloid deposition, which got significantly reduced in the ?-sitosterol treated group. Conclusion: AlCl3 was effectively employed to induce a cognitive deficit in mice, resulting in neurochemical changes and cognitive decline. ?-sitosterol treatment mitigated AlCl3-mediated cognitive impairment. � 2023 Bentham Science Publishers.Item Recent advances in molecular pathways and therapeutic implications targeting neuroinflammation for Alzheimer�s disease(Springer Science and Business Media Deutschland GmbH, 2021-11-23T00:00:00) Dhapola, Rishika; Hota, Subhendu Shekhar; Sarma, Phulen; Bhattacharyya, Anusuya; Medhi, Bikash; Reddy, Dibbanti HariKrishnaAlzheimer�s disease (AD) is a major contributor of dementia leading to the degeneration of neurons in the brain with major symptoms like loss of memory and learning. Many evidences suggest the involvement of neuroinflammation in the pathology of AD. Cytokines including TNF-? and IL-6 are also found increasing the BACE1 activity and expression of NF?B resulting in generation of A? in AD brain. Following the interaction of A? with microglia and astrocytes, other inflammatory molecules also get translocated to the site of inflammation by chemotaxis and exaggerate neuroinflammation. Various pathways like NF?B, p38 MAPK, Akt/mTOR, caspase, nitric oxide and COX trigger microglia to release inflammatory cytokines. PPAR? agonists like pioglitazone increases the phagocytosis of A? and reduces inflammatory cytokine IL-1?. Celecoxib and roficoxib like selective COX-2 inhibitors also ameliorate neuroinflammation. Non-selective COX inhibitor indomethacin is also potent inhibitor of inflammatory mediators released from microglia. Mitophagy process is considered quite helpful in reducing inflammation due to microglia as it promotes the phagocytosis of over activated microglial cells and other inflammatory cells. Mitophagy induction is also beneficial in the removal of damaged mitochondria and reduction of infiltration of inflammatory molecules at the site of accumulation of the damaged mitochondria. Targeting these pathways and eventually ameliorating the activation of microglia can mitigate neuroinflammation and come out as a better therapeutic option for the treatment of Alzheimer�s disease. � 2021, The Author(s), under exclusive licence to Springer Nature Switzerland AG.Item Recent Advances in Molecular Pathways and Therapeutic Implications Targeting Mitochondrial Dysfunction for Alzheimer�s Disease(Springer, 2021-11-02T00:00:00) Dhapola, Rishika; Sarma, Phulen; Medhi, Bikash; Prakash, Ajay; Reddy, Dibbanti HariKrishnaAlzheimer�s disease (AD) is a neurodegenerative disorder which leads to mental deterioration due to aberrant accretion of misfolded proteins in the brain. According to mitochondrial cascade hypothesis, mitochondrial dysfunction is majorly involved in the pathogenesis of AD. Many drugs targeting mitochondria to treat and prevent AD are in different phases of clinical trials for the evaluation of safety and efficacy as mitochondria are involved in various cellular and neuronal functions. Mitochondrial dynamics is regulated by fission and fusion processes mediated by dynamin-related protein (Drp1). Inner membrane fusion takes place by OPA1 and outer membrane fusion is facilitated by mitofusin1 and mitofusin2 (Mfn1/2). Excessive calcium release also impairs mitochondrial functions; to overcome this, calcium channel blockers like nilvadipine are used. Another process acting as a regulator of mitochondrial function is mitophagy which is involved in the removal of damaged and non-functional mitochondria however this process is also altered in AD due to mutations in Presenilin1 (PS1) and Amyloid Precursor Protein (APP) gene. Mitochondrial dynamics is altered in AD which led to the discovery of various fission protein (like Drp1) inhibitors and drugs that promote fusion. Modulations in AMPK, SIRT1 and Akt pathways can also come out to be better therapeutic strategies as these pathways regulate functions of mitochondria. Oxidative phosphorylation is major generator of Reactive Oxygen Species (ROS) leading to mitochondrial damage; therefore reduction in production of ROS by using antioxidants like MitoQ, Curcumin and Vitamin Eis quiteeffective. � 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.Item Neuroprotection through G-CSF: recent advances and future viewpoints(Springer Science and Business Media Deutschland GmbH, 2021-01-02T00:00:00) Rahi, Vikrant; Jamwal, Sumit; Kumar, PuneetGranulocyte-colony stimulating factor (G-CSF), a member of the cytokine family of hematopoietic growth factors, is 19.6�kDa glycoprotein which is responsible for the proliferation, maturation, differentiation, and survival of neutrophilic granulocyte lineage. Apart from its proven clinical application to treat chemotherapy-associated neutropenia, recent pre-clinical studies have highlighted the neuroprotective roles of G-CSF i.e., mobilization of haemopoietic stem cells, anti-apoptotic, neuronal differentiation, angiogenesis and anti-inflammatory in animal models of neurological disorders. G-CSF is expressed by numerous cell types including neuronal, immune and endothelial cells. G-CSF is released in autocrine manner and binds to its receptor G-CSF-R which further activates numerous signaling transduction pathways including PI3K/AKT, JAK/STAT and MAP kinase, and thereby promote neuronal survival, proliferation, differentiation, mobilization of hematopoietic stem and progenitor cells. The expression of G-CSF receptors (G-CSF-R) in the different brain regions and their upregulation in response to neuronal insult indicates the autocrine protective signaling mechanism of G-CSF by inhibition of apoptosis, inflammation, and stimulation of neurogenesis. These observed neuroprotective effects of G-CSF makes it an attractive target to mitigate neurodegeneration associated with neurological disorders. The objective of the review is to highlight and summarize recent updates on G-CSF as a therapeutically versatile neuroprotective agent along with mechanisms of action as well as possible clinical applications in neurodegenerative disorders including AD, PD and HD. � 2021, Maj Institute of Pharmacology Polish Academy of Sciences.