Department Of Pharmacology
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Item Endoplasmic reticulum stress in Alzheimer's disease: Molecular mechanisms and therapeutic prospects(Elsevier Inc., 2023-07-29T00:00:00) Nagar, Pushank; Sharma, Prajjwal; Dhapola, Rishika; Kumari, Sneha; Medhi, Bikash; HariKrishnaReddy, DibbantiAlzheimer's disease (AD) is a progressive neurodegenerative condition that leads to memory loss and cognitive impairment over time. It is characterized by protein misfolding as well as prolonged cellular stress, such as perturbing calcium homeostasis and redox management. Numerous investigations have proven that endoplasmic reticulum failure may exhibit exacerbation of AD pathogenesis in AD patients, in-vivo and in-vitro models. The endoplasmic reticulum (ER) participates in a variety of biological functions including folding of protein, quality control, cholesterol production, and maintenance of calcium balance. A diverse range of physiological, pathological and pharmacological substances can interfere with ER activity and thus lead to exaggeration of ER stress. The unfolded protein response (UPR), an intracellular signaling network is stimulated due to ER stress. Three stress sensors found in the endoplasmic reticulum, the PERK, ATF6, and IRE1 transducers detect protein misfolding in the ER and trigger UPR, a complex system to maintain homeostasis. ER stress is linked to many of the major pathological processes that are seen in AD, including presenilin1 and 2 (PS1 and PS2) gene mutation, tau phosphorylation and ?-amyloid formation. The role of ER stress and UPR in the pathophysiology of AD implies that they can be employed as potent therapeutic target. This study shows the relationship between ER and AD and how the pathogenesis of AD is influenced by the impact of ER stress. An effective method for the prevention or treatment of AD may involve therapeutic strategies that modify ER stress pathways. � 2023 Elsevier Inc.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 Insights into receptor tyrosine kinases signaling in neurodegenerative disorders: opportunities and translational perspectives(Elsevier, 2023-07-06T00:00:00) Randhawa, Puneet Kaur; Jaggi, Amteshwar Singh; Bali, AnjanaReceptor tyrosine kinases (RTKs) are a group of membrane-bound receptors comprising of extracellular ligand-binding domain, a transmembrane domain, and an intracellular catalytic domain. RTKs play a crucial role in various cellular processes including cellular growth, motility, cell differentiation, and cell metabolism. The dysregulation of RTK activity is a contributing factor in the progression of many neurodegenerative disorders. Studies revealed the alterations rearranged during transfection, epidermal growth factor receptor 1, vascular endothelial growth factor-B TAM receptors, and tropomyosin receptor kinase in neurodegenerative disorders. Further, PI3K/Akt/GSK-3? and Wnt/catenin signaling pathways are found to be major pathways for neuronal survival and neurite outgrowth induced by RTKs. This chapter summarizes the most important aspects of RTK subfamilies and their intraneuronal signaling mechanisms in different neurodegenerative disorders. The understanding of the fundamental mechanisms of RTKs in neurodegenerative disorders has important implications for the selection of a suitable neuroprotective agent. � 2023 Elsevier Inc. All rights reserved.Item Antiplatelet drugs: Potential therapeutic options for the management of neurodegenerative diseases(John Wiley and Sons Inc, 2023-05-03T00:00:00) Beura, Samir K.; Dhapola, Rishika; Panigrahi, Abhishek R.; Yadav, Pooja; Kumar, Reetesh; Reddy, Dibbanti H.; Singh, Sunil K.The blood platelet plays an important role but often remains under-recognized in several vascular complications and associated diseases. Surprisingly, platelet hyperactivity and hyperaggregability have often been considered the critical risk factors for developing vascular dysfunctions in several neurodegenerative diseases (NDDs) like Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. In addition, platelet structural and functional impairments promote prothrombotic and proinflammatory environment that can aggravate the progression of several NDDs. These findings provide the rationale for using antiplatelet agents not only to prevent morbidity but also to reduce mortality caused by NDDs. Therefore, we thoroughly review the evidence supporting the potential pleiotropic effects of several novel classes of synthetic antiplatelet drugs, that is, cyclooxygenase inhibitors, adenosine diphosphate receptor antagonists, protease-activated receptor blockers, and glycoprotein IIb/IIIa receptor inhibitors in NDDs. Apart from this, the review also emphasizes the recent developments of selected natural antiplatelet phytochemicals belonging to key classes of plant-based bioactive compounds, including polyphenols, alkaloids, terpenoids, and flavonoids as potential therapeutic candidates in NDDs. We believe that the broad analysis of contemporary strategies and specific approaches for plausible therapeutic treatment for NDDs presented in this review could be helpful for further successful research in this area. � 2023 Wiley Periodicals LLC.Item Apoptosis in Alzheimer�s disease: insight into the signaling pathways and therapeutic avenues(Springer, 2023-04-26T00:00:00) Kumari, Sneha; Dhapola, Rishika; Reddy, Dibbanti HariKrishnaAlzheimer�s disease (AD) is characterized by the accumulation of hyperphosphorylated tau and amyloid-? (A?) protein resulting in synaptic loss and apoptosis. A? and tau deposition trigger apoptotic pathways that result in neuronal death. Apoptosis is considered to be responsible for manifestations associated with AD under pathological conditions. It regulates via extrinsic and intrinsic pathways. It activates various proteins including Bcl-2 family proteins like Bax, Bad, Bid, Bcl-XS, Bcl-XL and caspases comprising of initiator, effector and inflammatory caspases carried out through a cascade of events that finally lead to cell disintegration. The apoptotic elements interact with trophic factors, signaling molecules including Ras-ERK, JNK, GSK-3?, BDNF/TrkB/CREB and PI3K/AKT/mTOR. Ras-ERK signaling is involved in the progression of cell cycle and apoptosis. JNK pathway is also upregulated in AD which results in decreased expression of anti-apoptotic proteins. JAK-STAT triggers caspase-3 mediated apoptosis leading to neurodegeneration. The imbalance between autophagy and apoptosis is regulated by PI3K/Akt/mTOR pathway. GSK-3? is involved in the stimulation of pro-apoptotic factors resulting in dysregulation of apoptosis. Drugs like filgrastim, epigallocatechin gallate, curcumin, nicergoline and minocycline are under development which target these pathways and modulate the disease condition. This study sheds light on apoptotic pathways that are cardinal for neuronal survival and perform crucial role in the occurrence of AD along with the trends in therapeutics targeting apoptosis induced AD. To develop prospective treatments for AD, it is desirable to elucidate potential targets including restoration apoptotic balance, regulation of caspases, Bcl-2 and other crucial proteins involved in apoptosis mediated AD. � 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.Item Redefining oxidative stress in Alzheimer's disease: Targeting platelet reactive oxygen species for novel therapeutic options(Elsevier Inc., 2022-08-01T00:00:00) Beura, Samir Kumar; Dhapola, Rishika; Panigrahi, Abhishek Ramachandra; Yadav, Pooja; Reddy, Dibbanti Harikrishna; Singh, Sunil KumarAlzheimer's disease (AD), a progressive neurodegenerative disorder, is considered one of the most common causes of dementia worldwide, accounting for about 80 % of all dementia cases. AD is manifested by the extraneuronal deposition of senile plaques of amyloid beta (A?) and intraneuronal accumulation of neurofibrillary tangles of phosphorylated tau. The impaired proteostasis of these filamentous A? and tau is significantly regulated by reactive oxygen species (ROS). ROS-induced oxidative stress (OS) is the cardinal cause behind neuroinflammation-triggered neurodegeneration during AD. Besides ROS-induced neuro-inflammation, AD is also associated with cerebrovascular dysfunction, where platelet primarily plays a significant role in blood-vessel integrity and tissue repair. Though platelets are the circulatory cell fragments that play predominant roles in thrombosis and hemostasis, their contributions to other physiological functions are also being elucidated. Surprisingly, platelets contribute about 90 % of the circulatory A? and share striking similarities with neurons in several aspects, including different neurotransmitters and their cognate receptors, thus considering platelets as potential peripheral models for AD. Interestingly, platelet structural and functional dysfunctions are evident in AD, where ROS production is associated with platelet hyperactivity. Although activated platelet carries several vital enzymes and immunomodulatory molecules, which can potentially exacerbate OS-mediated neuronal damage, and neurodegeneration, their mechanism of action and mode of progression, are still obscure. Therefore, in this review, we have described the detailed role of OS and platelet in AD, addressing the therapeutic approach and molecular mechanism of platelet-mediated ROS generation as a contributing factor in aggravating the disease. � 2022 Elsevier Inc.