Insight into the pathophysiological advances and molecular mechanisms underlying cerebral stroke: current status.

Molecular pathways involved in cerebral stroke are diverse. The major pathophysiological events that are observed in stroke comprises of excitotoxicity, oxidative stress, mitochondrial damage, endoplasmic reticulum stress, cellular acidosis, blood-brain barrier disruption, neuronal swelling and neuronal network mutilation. Various biomolecules are involved in these pathways and several major proteins are upregulated and/or suppressed following stroke. Different types of receptors, ion channels and transporters are activated. Fluctuations in levels of various ions and neurotransmitters have been observed. Cells involved in immune responses and various mediators involved in neuro-inflammation get upregulated progressing the pathogenesis of the disease. Despite of enormity of the problem, there is not a single therapy that can limit infarction and neurological disability due to stroke. This is because of poor understanding of the complex interplay between these pathophysiological processes. This review focuses upon the past to present research on pathophysiological events that are involved in stroke and various factors that are leading to neuronal death following cerebral stroke. This will pave a way to researchers for developing new potent therapeutics that can aid in the treatment of cerebral stroke.

Update on monkeypox virus infection: Focusing current treatment and prevention approaches.

BACKGROUND: While the world is still facing the global pandemic COVID-19, another zoonosis monkeypox (Mpox) has emerged posing a great threat to society. Insight into the pathogenesis, symptoms, and management strategies will aid in the development of potent therapeutics for the treatment of monkeypox virus infection. OBJECTIVES: To get insight into the current treatment and prevention strategies will aid in effectively coping with the disease. METHODS: For obtaining information regarding the ongoing treatment and prevention strategies and the drugs under pipeline, we referred to Google Scholar, Pub Med, Pub Chem, and WHO official site. RESULTS: There are a few drugs that came out to be effective for the treatment of Mpox. Tecovirimat acts by inhibiting viral replication and viral wrapping. Another drug is cidofovir, which hinders the activity of viral DNA polymerase but has the drawback of nephrotoxicity. To overcome this, a conjugate of cidofovir is being used-known as brincidofovir-which has a similar mechanism as cidofovir but lesser toxicity. Ribavirin acts via inhibiting inosine monophosphate dehydrogenase (IMPDPH) thus disrupting viral translation. It also interferes with helicase activity. Tiazofurin, Adenosine N1 oxide, and HPMPA have shown efficacy in in-vitro studies by inhibiting IMPDH, DNA polymerase, and viral mRNA translation respectively. In-silico studies have proven the effect of nilotinib, simeprevir, and dihydroergotamine for Mpox treatment. They have shown binding affinity for proteins required for the growth and release of MPXV. Vaccines have also been employed for the prevention of Mpox, which includes JYNNEOS, ACAM2000, and VIGIV. CONCLUSION: This review highlights the pathogenesis of the virus, disease manifestations, drugs, and vaccines that are being used and those under pipeline for the treatment and prevention of Mpox.

Oxidative stress in Alzheimer's disease: current knowledge of signaling pathways and therapeutics.

Alzheimer's disease's pathophysiology is still a conundrum. Growing number of evidences have elucidated the involvement of oxidative stress in the pathology of AD rendering it a major target for therapeutic development. Reactive oxygen species (ROS) generated by altered mitochondrial function, dysregulated electron transport chain and other sources elevate aggregated Aß and neurofibrillary tangles which further stimulating the production of ROS. Oxidative stress induced damage to lipids, proteins and DNA result in neuronal death which leads to AD. In addition, oxidative stress induces apoptosis that is triggered by the modulation of ERK1/2 and Nrf2 pathway followed by increased GSK-3ß expression and decreased PP2A activity. Oxidative stress exaggerates disease condition by interfering with various signaling pathways like RCAN1, CREB/ERK, Nrf2, PP2A, NFκB and PI3K/Akt. Studies have reported the role of TNF-α in oxidative stress stimulation that has been regulated by drugs like etanercept increasing the level of anti-oxidants. Other drugs like pramipexole, memantine, carvedilol, and melatonin have been reported to activate CREB/RCAN1 and Nrf2 pathways. In line with this, epigallocatechin gallate and genistein also target Nrf2 and CREB pathway leading to activation of downstream pathways like ARE and Keap1 which ameliorate oxidative stress condition. Donepezil and resveratrol reduce oxidative stress and activate AMPK pathway along with PP2A activation thus promoting tau dephosphorylation and neuronal survival. This study describes in detail the role of oxidative stress in AD, major signaling pathways involving oxidative stress induced AD and drugs under development targeting these pathways which may aid in therapeutic advances for AD.

Insight into the emerging and common experimental in-vivo models of Alzheimer's disease.

Alzheimer's disease (AD) is a multifactorial, rapidly progressing neurodegenerative disorder. As the exact cause of the disease is still unclear, the drug development is very challenging. This review encompasses the commonly used AD models involving various chemicals, heavy metals and endogenous substances induced models and the transgenic models. It also provides insight into the reliable emerging models of AD that may overcome the shortcomings associated with available models. Chemicals like streptozotocin, scopolamine, colchicine and okadaic acid render the animal susceptible to neuroinflammation and oxidative stress induced neurodegeneration along with amyloid-ß deposition and tau hyperphosphorylation. Similarly, endogenous substances like acrolein and amyloid-ß 1-42 are efficient in inducing the major pathologies of AD. Heavy metals like aluminum and fluoride and mixture of these have been reported to induce neurotoxicity therefore are used as animal models for AD. Transgenic models developed as a result of knock-in or knock-out of certain genes associated with AD including PDAPP, APP23, Tg2576, APP/PS1, 3 × Tg and 5 × FAD have also been incorporated in this study. Further, emerging and advanced pathomimetic models of AD are provided particular interest here which will add on to the current knowledge of animal models and may aid in the drug development process and deepen our understanding related to AD pathogenesis. These newly discovered models include oAß25-35 model, transgenic model expressing 82-kDa ChAT, oDGal mouse and APP knock-in rat. This study may aid in the selection of suitable model for development of novel potent therapeutics and for exploring detailed pathogenic mechanism of AD.

Environmental Toxins and Alzheimer's Disease: a Comprehensive Analysis of Pathogenic Mechanisms and Therapeutic Modulation.

Alzheimer's disease is a leading cause of mortality worldwide. Inorganic and organic hazards, susceptibility to harmful metals, pesticides, agrochemicals, and air pollution are major environmental concerns. As merely 5% of AD cases are directly inherited indicating that these environmental factors play a major role in disease development. Long-term exposure to environmental toxins is believed to progress neuropathology, which leads to the development of AD. Numerous in-vitro and in-vivo studies have suggested the harmful impact of environmental toxins at cellular and molecular level. Common mechanisms involved in the toxicity of these environmental pollutants include oxidative stress, neuroinflammation, mitochondrial dysfunction, abnormal tau, and APP processing. Increased expression of GSK-3ß, BACE-1, TNF-α, and pro-apoptotic molecules like caspases is observed upon exposure to these environmental toxins. In addition, the expression of neurotrophins like BDNF and GAP-43 have been found to be reduced as a result of toxicity. Further, modulation of signaling pathways involving PARP-1, PGC-1α, and MAPK/ERK induced by toxins have been reported to contribute in AD pathogenesis. These pathways are a promising target for developing novel AD therapeutics. Drugs like epigallocatechin-gallate, neflamapimod, salsalate, dexmedetomidine, and atabecestat are in different phases of clinical trials targeting the pathways for possible treatment of AD. This review aims to culminate the correlation between environmental toxicants and AD development. We emphasized upon the signaling pathways involved in the progression of the disease and the therapeutics under clinical trial targeting the altered pathways for possible treatment of AD.

Endoplasmic reticulum stress in Alzheimer's disease: Molecular mechanisms and therapeutic prospects.

Alzheimer'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 ß-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.

Antiplatelet drugs: Potential therapeutic options for the management of neurodegenerative diseases.

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.

Apoptosis in Alzheimer's disease: insight into the signaling pathways and therapeutic avenues.

Alzheimer's disease (AD) is characterized by the accumulation of hyperphosphorylated tau and amyloid-ß (Aß) protein resulting in synaptic loss and apoptosis. Aß 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-3ß, 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-3ß 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.

Neuroinflammation in Alzheimer's Disease: Current Progress in Molecular Signaling and Therapeutics.

Alzheimer's disease, a neurodegenerative disease with amyloid beta accumulation as a major hallmark, has become a dire global health concern as there is a lack of clear understanding of the causative agent. It is a major cause of dementia which is increasing exponentially with age. Alzheimer's disease is marked by tau hyperphosphorylation and amyloid beta accumulation that robs people of their memories. Amyloid beta deposition initiated a spectrum of microglia-activated neuroinflammation, and microglia and astrocyte activation elicited expressions of various inflammatory and anti-inflammatory cytokines. Neuroinflammation is one of the cardinal features of Alzheimer's disease. Pro-inflammatory cytokine signaling plays multifarious roles in neurodegeneration and neuroprotection. Induction of proinflammatory signaling leads to discharge of immune mediators which affect functions of neurons and cause cell death. Sluggish anti-inflammatory system also contributes to neuroinflammation. Numerous pathways like NFκB, p38 MAPK, Akt/mTOR, caspase, nitric oxide, and COX are involved in triggering brain immune cells like astrocytes and microglia to secrete inflammatory cytokines such as tumor necrosis factor, interleukins, and chemokines and participate in Alzheimer's disease pathology. PPAR-γ agonists tend to boost the phagocytosis of amyloid beta and decrease the inflammatory cytokine IL-1ß. Recent findings suggest the cross-link between gut microbiota and neuroinflammation contributing in AD which has been explained in this study. The role of cellular, molecular pathways and involvement of inflammatory mediators in neuroinflammation has also been described; targeting them could be a potential therapeutic strategy for treatment of AD.

Redefining oxidative stress in Alzheimer's disease: Targeting platelet reactive oxygen species for novel therapeutic options.

Alzheimer'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 (Aß) and intraneuronal accumulation of neurofibrillary tangles of phosphorylated tau. The impaired proteostasis of these filamentous Aß 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 Aß 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.

Recent Advances in Molecular Pathways and Therapeutic Implications Targeting Mitochondrial Dysfunction for Alzheimer's Disease.

Alzheimer'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.

Recent advances in molecular pathways and therapeutic implications targeting neuroinflammation for Alzheimer's disease.

Alzheimer'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-α and IL-6 are also found increasing the BACE1 activity and expression of NFκB resulting in generation of Aß in AD brain. Following the interaction of Aß with microglia and astrocytes, other inflammatory molecules also get translocated to the site of inflammation by chemotaxis and exaggerate neuroinflammation. Various pathways like NFκB, p38 MAPK, Akt/mTOR, caspase, nitric oxide and COX trigger microglia to release inflammatory cytokines. PPARγ agonists like pioglitazone increases the phagocytosis of Aß and reduces inflammatory cytokine IL-1ß. 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.