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Alzheimer's disease (AD) and Diabetes mellitus (DM) exhibit comparable pathophysiological pathways. Genetic abnormalities in APP, PS-1, and PS-2 are linked to AD, with diagnostic aid from CSF and blood biomarkers. Insulin dysfunction, termed "type 3 diabetes mellitus" in AD, involves altered insulin signalling and neuronal shrinkage. Insulin influences beta-amyloid metabolism, exacerbating neurotoxicity in AD and amyloid production in DM. Both disorders display impaired glucose transporter expression, hastening cognitive decline. Mitochondrial dysfunction and Toll-like receptor 4-mediated inflammation worsen neurodegeneration in both diseases. ApoE4 raises disease risk, especially when coupled with dyslipidemia common in DM. Targeting shared pathways like insulin-degrading enzyme activation and HSP60 holds promise for therapeutic intervention. Recognizing these interconnected mechanisms underscores the imperative for developing tailored treatments addressing the overlapping pathophysiology of AD and DM, offering potential avenues for more effective management of both conditions.
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Mitochondria are singular cell organelles essential for many cellular functions, which includes responding to stress, regulating calcium levels, maintaining protein homeostasis, and coordinating apoptosis response. The vitality of cells, therefore, hinges on the optimal functioning of these dynamic organelles. Mitochondrial Quality Control Mechanisms (MQCM) play a pivotal role in ensuring the integrity and functionality of mitochondria. Perturbations in these mechanisms have been closely associated with the pathogenesis of neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and amyotrophic lateral sclerosis. Compelling evidence suggests that targeting specific pathways within the MQCM could potentially offer a therapeutic avenue for rescuing mitochondrial integrity and mitigating the progression of neurodegenerative diseases. The intricate interplay of cellular stress, protein misfolding, and impaired quality control mechanisms provides a nuanced understanding of the underlying pathology. Consequently, unravelling the specific MQCM dysregulation in neurodegenerative disorders becomes paramount for developing targeted therapeutic strategies. This review delves into the impaired MQCM pathways implicated in neurodegenerative disorders and explores emerging therapeutic interventions. By shedding light on pharmaceutical and genetic manipulations aimed at restoring MQCM efficiency, the discussion aims to provide insights into novel strategies for ameliorating the progression of neurodegenerative diseases. Understanding and addressing mitochondrial quality control mechanisms not only underscore their significance in cellular health but also offer a promising frontier for advancing therapeutic approaches in the realm of neurodegenerative disorders.
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Alzheimer's disease (AD) is a complex neurological ailment that causes cognitive decline and memory loss. Cholesterol metabolism dysregulation has emerged as a crucial element in AD pathogenesis, contributing to the formation of amyloid-beta (Aß) plaques and tau tangles, the disease's hallmark neuropathological characteristics. Thus, targeting cholesterol metabolism has gained attention as a potential therapeutic method for Alzheimer's disease. Phytoremedies, which are generated from plants and herbs, have shown promise as an attainable therapeutic option for Alzheimer's disease. These remedies contain bioactive compounds like phytochemicals, flavonoids, and polyphenols, which have demonstrated potential in modulating cholesterol metabolism and related pathways. This comprehensive review explores the modulation of cholesterol metabolism by phytoremedies in AD. It delves into the role of cholesterol in brain function, highlighting disruptions observed in AD. Additionally, it examines the underlying molecular mechanisms of cholesterol-related pathology in AD. The review emphasizes the significance of phytoremedies as a potential therapeutic intervention for AD. It discusses the drawbacks of current treatments and the need for alternative strategies addressing cholesterol dysregulation and its consequences. Through an in-depth analysis of specific phytoremedies, the review presents compelling evidence of their potential benefits. Molecular mechanisms underlying phytoremedy effects on cholesterol metabolism are examined, including regulation of cholesterol-related pathways, interactions with Aß pathology, influence on tau pathology, and anti-inflammatory effects. The review also highlights challenges and future perspectives, emphasizing standardization, clinical evidence, and personalized medicine approaches to maximize therapeutic potential in AD treatment. Overall, phytoremedies offer promise as a potential avenue for AD management, but further research and collaboration are necessary to fully explore their efficacy, safety, and mechanisms of action.
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Doença de Alzheimer , Colesterol , Doença de Alzheimer/metabolismo , Doença de Alzheimer/tratamento farmacológico , Humanos , Colesterol/metabolismo , Animais , Fitoterapia/métodos , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacosRESUMO
The present study aimed to investigate the role of agmatine in the neurobiology underlying memory impairment during ethanol withdrawal in rats. Sprague-Dawley rats were subjected to a 21-day chronic ethanol exposure regimen (2.4 % w/v ethanol for 3 days, 4.8 % w/v for the next 4 days, and 7.2 % w/v for the following 14 days), followed by a withdrawal period. Memory impairment was assessed using the passive avoidance test (PAT) at 24, 48, and 72 h post-withdrawal. The ethanol-withdrawn rats displayed a significant decrease in step-through latency in the PAT, indicative of memory impairment at 72 h post-withdrawal. However, administration of agmatine (40 µg/rat) and its modulators (L-arginine, arcaine, and amino-guanidine) significantly increases the latency time in the ethanol-withdrawn rats, demonstrating the attenuation of memory impairment. Further, pretreatment with imidazoline receptor agonists enhances agmatine's effects, while antagonists block them, implicating imidazoline receptors in agmatine's actions. Neurochemical analysis in ethanol-withdrawn rats reveals dysregulated glutamate and GABA levels, which was attenuated by agmatine and its modulators. By examining the effects of agmatine administration and modulators of endogenous agmatine, the study aimed to shed light on the potential therapeutic implications of agmatinergic signaling in alcohol addiction and related cognitive deficits. Thus, the present findings suggest that agmatine administration and modulation of endogenous agmatine levels hold potential as therapeutic strategies for managing alcohol addiction and associated cognitive deficits. Understanding the neurobiology underlying these effects paves the way for the development of novel interventions targeting agmatinergic signaling in addiction treatment.
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Agmatina , Disfunção Cognitiva , Etanol , Ratos Sprague-Dawley , Síndrome de Abstinência a Substâncias , Animais , Agmatina/farmacologia , Agmatina/uso terapêutico , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Síndrome de Abstinência a Substâncias/psicologia , Masculino , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Ratos , Biguanidas/farmacologia , Ácido Glutâmico/metabolismo , Arginina/farmacologia , Ácido gama-Aminobutírico/metabolismo , Receptores de Imidazolinas/metabolismo , Receptores de Imidazolinas/agonistas , Aprendizagem da Esquiva/efeitos dos fármacosRESUMO
Neurodegenerative disorders are distinguished by the progressive loss of anatomically or physiologically relevant neural systems. Atypical mitochondrial morphology and metabolic malfunction are found in many neurodegenerative disorders. Alteration in mitochondrial function can occur as a result of aberrant mitochondrial DNA, altered nuclear enzymes that interact with mitochondria actively or passively, or due to unexplained reasons. Mitochondria are intimately linked to the Endoplasmic reticulum (ER), and ER-mitochondrial communication governs several of the physiological functions and procedures that are disrupted in neurodegenerative disorders. Numerous researchers have associated these disorders with ER-mitochondrial interaction disturbance. In addition, aberrant mitochondrial DNA mutation and increased ROS production resulting in ionic imbalance and leading to functional and structural alterations in the brain as well as cellular damage may have an essential role in disease progression via mitochondrial malfunction. In this review, we explored the evidence highlighting the role of mitochondrial alterations in neurodegenerative pathways in most serious ailments, including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD).
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Mitocôndrias , Doenças Neurodegenerativas , Humanos , Doenças Neurodegenerativas/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Animais , Retículo Endoplasmático/metabolismo , DNA Mitocondrial/metabolismo , DNA Mitocondrial/genéticaRESUMO
Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by progressive cognitive decline and a significant societal burden. Despite extensive research and efforts of the multidisciplinary scientific community, to date, there is no cure for this debilitating disease. Moreover, the existing pharmacotherapy for AD only provides symptomatic support and does not modify the course of the illness or halt the disease progression. This is a significant limitation as the underlying pathology of the disease continues to progress leading to the deterioration of cognitive functions over time. In this milieu, there is a growing need for the development of new and more efficacious treatments for AD. Agmatine, a naturally occurring molecule derived from L-arginine, has emerged as a potential therapeutic agent for AD. Besides this, agmatine has been shown to modulate amyloid beta (Aß) production, aggregation, and clearance, key processes implicated in AD pathogenesis. It also exerts neuroprotective effects, modulates neurotransmitter systems, enhances synaptic plasticity, and stimulates neurogenesis. Furthermore, preclinical and clinical studies have provided evidence supporting the cognition-enhancing effects of agmatine in AD. Therefore, this review article explores the promising role of agmatine in AD pathology and cognitive function. However, several limitations and challenges exist, including the need for large-scale clinical trials, optimal dosing, and treatment duration. Future research should focus on mechanistic investigations, biomarker studies, and personalized medicine approaches to fully understand and optimize the therapeutic potential of agmatine. Augmenting the use of agmatine may offer a novel approach to address the unmet medical need in AD and provide cognitive enhancement and disease modification for individuals affected by this disease.
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Agmatina , Doença de Alzheimer , Disfunção Cognitiva , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides , Agmatina/farmacologia , Agmatina/uso terapêutico , CogniçãoRESUMO
Cardiotoxicity is a well-known adverse effect of cancer-related therapy that has a significant influence on patient outcomes and quality of life. The use of antineoplastic drugs to treat colorectal cancers (CRCs) is associated with a number of undesirable side effects including cardiac complications. For both sexes, CRC ranks second and accounts for four out of every ten cancer deaths. According to the reports, almost 39% of patients with colorectal cancer who underwent first-line chemotherapy suffered cardiovascular impairment. Although 5-fluorouracil is still the backbone of chemotherapy regimen for colorectal, gastric, and breast cancers, cardiotoxicity caused by 5-fluorouracil might affect anywhere from 1.5% to 18% of patients. The precise mechanisms underlying cardiotoxicity associated with CRC treatment are complex and may involve the modulation of various signaling pathways crucial for maintaining cardiac health including TKI ErbB2 or NRG-1, VEGF, PDGF, BRAF/Ras/Raf/MEK/ERK, and the PI3/ERK/AMPK/mTOR pathway, resulting in oxidative stress, mitochondrial dysfunction, inflammation, and apoptosis, ultimately damaging cardiac tissue. Thus, the identification and management of cardiotoxicity associated with CRC drug therapy while minimizing the negative impact have become increasingly important. The purpose of this review is to catalog the potential cardiotoxicities caused by anticancer drugs and targeted therapy used to treat colorectal cancer as well as strategies focused on early diagnosing, prevention, and treatment of cardiotoxicity associated with anticancer drugs used in CRC therapy.
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Avenanthramides (Avns) and their derivatives, a group of polyphenolic compounds found abundantly in oats (Avena sativa Linn.), have emerged as promising candidates for neuroprotection due to their immense antioxidant, anti-inflammatory, and anti-apoptotic properties. Neurodegenerative diseases (NDDs), characterized by the progressive degeneration of neurons, present a significant global health burden with limited therapeutic options. The phosphoinositide 3-kinase (PI3K) signaling pathway plays a crucial role in cell survival, growth, and metabolism, making it an attractive target for therapeutic intervention. The dysregulation of PI3K signaling has been implicated in the pathogenesis of various NDDs including Alzheimer's and Parkinson's disease. Avns have been shown to modulate PI3K/AKT signaling, leading to increased neuronal survival, reduced oxidative stress, and improved cognitive function. This review explores the potential of Avn polyphenols as modulators of the PI3K signaling pathway, focusing on their beneficial effects against NDDs. Further, we outline the need for clinical exploration to elucidate the specific mechanisms of Avn action on the PI3K/AKT pathway and its potential interactions with other signaling cascades involved in neurodegeneration. Based on the available literature, using relevant keywords from Google Scholar, PubMed, Scopus, Science Direct, and Web of Science, our review emphasizes the potential of using Avns as a therapeutic strategy for NDDs and warrants further investigation and clinical exploration.
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Avena , Doenças Neurodegenerativas , Fosfatidilinositol 3-Quinases , Doenças Neurodegenerativas/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt , Grão Comestível , Fosfatidilinositol 3-QuinaseRESUMO
Biological researchers are seeing organelles in a new light. These cellular entities have been believed to be singular and distinctive structures that performed specialized purposes for a very long time. But in recentpast years, scientists have learned that organelles become dynamic and make physical contact. Additionally, Biological processes are regulated by organelles interactions and its alteration play an important role in cell malfunctioning and several pathologies, including neurodegenerative diseases. Mitochondrial-ER contact sites (MERCS) have received considerable attention in the domain of cell homeostasis and dysfunction, specifically in the area of neurodegeneration. This is largely due to the significant role of this subcellular compartment in a diverse array of vital cellular functions, including Ca2+ homeostasis, transport, bioenergetics and turnover, mitochondrial dynamics, apoptotic signaling, ER stress, and inflammation. A significant number of disease-associated proteins were found to physically interact with the ER-Mitochondria (ER-MT) interface, causing structural and/or functional alterations in this compartment. In this review, we summarize current knowledge about the structure and functions of the ER-MT contact sites, as well as the possible repercussions of their alteration in notable neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and fronto-temporal dementia. The constraints and complexities in defining the nature and origin of the highlighted defects in ER-MT communication, as well as their concise contribution to the neurodegenerative process, are illustrated in particular. The possibility of using MERCS as a potential drug target to prevent neuronal damage and ultimately neurodegeneration is the topic of our final discussion.
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Doenças Neurodegenerativas , Doença de Parkinson , Humanos , Retículo Endoplasmático/metabolismo , Mitocôndrias/metabolismo , Membranas Mitocondriais/metabolismo , Doenças Neurodegenerativas/metabolismo , Doença de Parkinson/patologiaRESUMO
Neurodegenerative diseases (NDD) are incurable and the most prevalent cognitive and motor disorders of elderly. Mitochondria are essential for a wide range of cellular processes playing a pivotal role in a number of cellular functions like metabolism, intracellular signaling, apoptosis, and immunity. A plethora of evidence indicates the central role of mitochondrial functions in pathogenesis of many aging related NDD. Considering how mitochondria function in neurodegenerative diseases, oxidative stress, and mutations in mtDNA both contribute to aging. Many substantial reports suggested the involvement of numerous contributing factors including, mitochondrial dysfunction, oxidative stress, mitophagy, accumulation of somatic mtDNA mutations, compromised mitochondrial dynamics, and transport within axons in neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis. Therapies therefore target fundamental mitochondrial processes such as energy metabolism, free-radical generation, mitochondrial biogenesis, mitochondrial redox state, mitochondrial dynamics, mitochondrial protein synthesis, mitochondrial quality control, and metabolism hold great promise to develop pharmacological based therapies in NDD. By emphasizing the most efficient pharmacological strategies to target dysfunction of mitochondria in the treatment of neurodegenerative diseases, this review serves the scientific community engaged in translational medical science by focusing on the establishment of novel, mitochondria-targeted treatment strategies.
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Doenças Neurodegenerativas , Humanos , Idoso , Doenças Neurodegenerativas/metabolismo , Mitocôndrias/metabolismo , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , DNA Mitocondrial/uso terapêutico , Estresse Oxidativo , EnvelhecimentoRESUMO
Mitochondria are the primary cellular energy generators, supplying the majority of adenosine triphosphate through oxidative phosphorylation, which is necessary for neuron function and survival. Mitophagy is the metabolic process of eliminating dysfunctional or redundant mitochondria. It is a type of autophagy and it is crucial for maintaining mitochondrial and neuronal health. Impaired mitophagy leads to an accumulation of damaged mitochondria and proteins leading to the dysregulation of mitochondrial quality control processes. Recent research shows the vital role of mitophagy in neurons and the pathogenesis of major neurodegenerative diseases. Mitophagy also plays a major role in the process of aging. This review describes the alterations that are being caused in the mitophagy process at the molecular level in aging and in neurodegenerative diseases, particularly Alzheimer's, Parkinson's, and Huntington's diseases and amyotrophic lateral sclerosis, also looks at how mitophagy can be exploited as a therapeutic target for these diseases.
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Protein misfolding causes aggregation and build-up in a variety of brain diseases. There are numeral molecules that are linked with the protein homeostasis mechanism. Molecular chaperones are one of such molecules that are responsible for protection against protein misfolded and aggregation-induced neurotoxicity. Many studies have explored the participation of molecular chaperones in Parkinson's disease, Alzheimer's disease, Amyotrophic lateral sclerosis, and Huntington's diseases. In this review, we highlighted the constructive role of molecular chaperones in neurological diseases characterized by protein misfolding and aggregation and their capability to control aberrant protein interactions at an early stage thus successfully suppressing pathogenic cascades. A comprehensive understanding of the protein misfolding associated with brain diseases and the molecular basis of involvement of chaperone against aggregation-induced cellular stress might lead to the progress of new therapeutic intrusion-related to protein misfolding and aggregation.
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Chaperonas Moleculares/metabolismo , Deficiências na Proteostase/patologia , Doença de Alzheimer/patologia , Esclerose Lateral Amiotrófica/patologia , Autofagia/fisiologia , Encéfalo/metabolismo , Doença de Huntington/patologia , Doença de Parkinson/patologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteostase/fisiologia , Ubiquitina/metabolismoRESUMO
One of the comorbid conditions in an individual with Alzheimer's disease is a sleep disorder. Clinical features of sleep disorders involve various sleep disturbances such as Obstructive Sleep Apnea (OSAS), Excessive Daytime Sleepiness (EDS), Rapid Eye Movement (REM), Breathing Disorders, Periodic limb movements in sleep (PLMS), etc. The primary tools used for the identification of such disturbances are Polysomnography (PSG) and Wrist actigraphy. This review will highlight and explains the different approaches used in the treatment of sleep disorders. Non-pharmacological treatments include Peter Hauri rules, sleep education program, and light therapy which play a key role in the regulation of sleep-wake cycles. Pharmacological therapy described in this article may be useful in treating sleep destruction in patients with Alzheimer's disease. Along with the Non-pharmacological and pharmacological treatment, here we discuss five commonly recognized plant-based nutraceuticals with hypothesized impact on sleep disorders: caffeine, chamomile, cherries, L-tryptophan, and valerian by the proper emphasis on the known mechanism of their action.
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Doença de Alzheimer , Distúrbios do Sono por Sonolência Excessiva , Transtornos do Sono-Vigília , Doença de Alzheimer/tratamento farmacológico , Humanos , Polissonografia , Sono , Transtornos do Sono-Vigília/tratamento farmacológicoRESUMO
Epilepsy is the most common neurological disorder, affecting nearly 50 million people worldwide. The condition can be manifested either due to genetic predisposition or acquired from acute insult which leads to alteration of cellular and molecular mechanisms. Evaluating the latest and the current knowledge in regard to the mechanisms underlying molecular and cellular alteration, hyperexcitability is a consequence of an imbalanced state wherein enhance excitatory glutamatergic and reduced inhibitory GABAergic signaling is considered to be accountable for seizures associated damage. However, neurodegeneration contributing to epileptogenesis has become increasingly appreciated. The components at the helm of neurodegenerative alterations during epileptogenesis include GABAergic neuronal and receptor changes, neuroinflammation, alteration in axonal transport, oxidative stress, excitotoxicity, and other cellular as well as functional changes. Targeting neurodegeneration with vitamin E as an antioxidant, anti-inflammatory and neuroprotective may prove to be one of the therapeutic approaches useful in managing epilepsy. In this review, we discuss and converse about the seizure-induced episodes as a link for the development of neurodegenerative and pathological consequences of epilepsy. We also put forth a summary of the potential intervention with vitamin E therapy in the management of epilepsy.
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Anticonvulsivantes/uso terapêutico , Ondas Encefálicas/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Epilepsia/tratamento farmacológico , Degeneração Neural , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Vitamina E/uso terapêutico , Animais , Anti-Inflamatórios/uso terapêutico , Anticonvulsivantes/efeitos adversos , Antioxidantes/uso terapêutico , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Epilepsia/epidemiologia , Epilepsia/metabolismo , Epilepsia/fisiopatologia , Humanos , Mediadores da Inflamação/metabolismo , Doenças Neurodegenerativas/epidemiologia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/fisiopatologia , Fármacos Neuroprotetores/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Prognóstico , Medição de Risco , Fatores de Risco , Transdução de Sinais , Vitamina E/efeitos adversosRESUMO
Chronic maternal ethanol exposure leads to poor intelligence, impaired cognition and array of neurological symptoms in offsprings and commonly referred as fetal alcohol spectrum disorder (FASD). Despite high prevalence and severity, the neurochemical basis of FASD remains largely unexplored. The present study evaluated the pharmacological effects of agmatine in cognitive deficits associated with FAS in rat's offsprings prenatally exposed to alcohol. Pregnant rats received ethanol in liquid modified diet during the entire gestational period of 21 days. Offsprings were treated with agmatine (20-80 mg/Kg, i.p.) during early postnatal days (PND: 21-35) and subsequently evaluated for anxiety in elevated plus maze (EPM), depression in forced swim test (FST) and learning and memory in Morris's water maze (MWM) during post adolescent phase. Hippocampal agmatine, BDNF, TNF-α and IL-6 levels were also analyzed in prenatally ethanol exposed pups. Offsprings prenatally exposed to ethanol demonstrated delayed righting reflex, reduced exploratory behavior along with anxiety, depression-like behavior and impaired memory. These behavioral abnormalities were correlated with a significant reduction in hippocampal agmatine and BDNF levels and elevation in TNF-α and IL-6 immunocontent. Chronic agmatine (40 and 80 mg/Kg, i.p.) administration for 15 days (PND: 21-35), improved entries and time spent in open arm of EPM, decreased immobility time in FST. It also reduced latency to reach the platform location; increased the number of entries, time spent in platform quadrant and also number of crossing over platform quadrant when subjected to MWM test in prenatally ethanol exposed offsprings. This study provides functional evidences for the therapeutic potential of agmatine in cognitive impairment and other neurological complications associated with FASD.