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1.
Arch Biochem Biophys ; 759: 110101, 2024 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-39029645

RESUMO

For diabetic patients it is crucial to constantly monitor blood glucose levels to mitigate complications due to hyperglycaemia, including neurological issues and cognitive impairments. This activity leads to psychological stress, called "diabetes distress," a problem for most patients living with diabetes. Diabetes distress can exacerbate the hyperglycaemia effects on brain and negatively impact the quality of life, but the underlying mechanisms remain poorly explored. We simulated diabetes distress in adult zebrafish by modelling hyperglycaemia, through exposure to dextrose solution, along with chronic unpredictable mild stress (CUMS), and evaluated brain redox homeostasis by assessing reactive oxygen species (ROS) content, the antioxidant system, and effects on mitochondrial biogenesis and fission/fusion processes. We also evaluated the total, cytosolic and nuclear content of nuclear factor erythroid 2-related factor 2 (NRF2), a critical regulator of redox balance, in the whole brain and total NRF2 in specific brain emotional areas. The combined CUMS + Dextrose challenge, but not the individual treatments, reduced total NRF2 levels in the entire brain, but strongly increased its levels in the nuclear fraction. Compensatory upregulation of antioxidant genes appeared inadequate to combat elevated levels of ROS, leading to lowering of the reduced glutathione content and total antioxidant capacity. CUMS + Dextrose treatment also upregulated transcription factors implicated in mitochondrial biogenesis and dynamics with a predominance of fission, which is consistent with increased oxidative stress. In conclusion, this study highlights the close interplay between hyperglycaemia and psychological distress causing overriding oxidative stress in the brain, rendering the organism vulnerable to the development of disease complications.

2.
Apoptosis ; 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38760516

RESUMO

Alzheimer's disease (AD), the most prevalent form of dementia, is characterized by progressive cognitive impairment accompanied by aberrant neuronal apoptosis. Reports suggest that the pro-apoptotic mammalian set20-like kinase 1/2 (MST1/2) instigates neuronal apoptosis via activating the Hippo signaling pathway under various stress conditions, including AD. However, whether inhibiting MST1/2 has any therapeutic benefits in AD remains unknown. Thus, we tested the therapeutic effects of intervening MST1/2 activation via the pharmacological inhibitor Xmu-mp-1 in a sporadic AD rat model. Sporadic AD was established in adult rats by intracerebroventricular streptozotocin (ICV-STZ) injection (3 mg/kg body weight). Xmu-mp-1 (0.5 mg/kg/body weight) was administered once every 48 h for two weeks, and Donepezil (5 mg/kg body weight) was used as a reference standard drug. The therapeutic effects of Xmu-mp-1 on ICV-STZ rats were determined through various behavioral, biochemical, histopathological, and molecular tests. At the behavioral level, Xmu-mp-1 improved cognitive deficits in sporadic AD rats. Further, Xmu-mp-1 treatment reduced STZ-associated tau phosphorylation, amyloid-beta deposition, oxidative stress, neurotoxicity, neuroinflammation, synaptic dysfunction, neuronal apoptosis, and neurodegeneration. Mechanistically, Xmu-mp-1 exerted these neuroprotective actions by inactivating the Hippo signaling while potentiating the Wnt/ß-Catenin signaling in the AD rats. Together, the results of the present study provide compelling support that Xmu-mp-1 negated the neuronal dysregulation in the rat model of sporadic AD. Therefore, inhibiting MST/Hippo signaling and modulating its crosstalk with the Wnt/ß-Catenin pathway can be a promising alternative treatment strategy against AD pathology. This is the first study providing novel mechanistic insights into the therapeutic use of Xmu-mp-1 in sporadic AD.

3.
Mitochondrion ; 76: 101885, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38643865

RESUMO

Mitochondria are the membrane-bound organelles producing energy for cellular metabolic processes. They orchestrate diverse cell signaling cascades regulating cellular homeostasis. This functional versatility may be attributed to their ability to regulate mitochondrial dynamics, biogenesis, and apoptosis. The Hippo pathway, a conserved signaling pathway, regulates various cellular processes, including mitochondrial functions. Through its effectors YAP and TAZ, the Hippo pathway regulates transcription factors and creates a seriatim process that mediates cellular metabolism, mitochondrial dynamics, and survival. Mitochondrial dynamics also potentially regulates Hippo signaling activation, indicating a bidirectional relationship between the two. This review outlines the interplay between the Hippo signaling components and the multifaceted role of mitochondria in cellular homeostasis under physiological and pathological conditions.


Assuntos
Via de Sinalização Hippo , Homeostase , Animais , Humanos , Mitocôndrias/metabolismo , Dinâmica Mitocondrial , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais
4.
Mol Nutr Food Res ; 68(13): e2300245, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38143280

RESUMO

BACKGROUND: Alzheimer's disease (AD) is the most prevalent dementia, affecting a large number of populations. Despite being under scrutiny for decades, an effective therapeutic option is still not available. METHODS AND RESULTS: This study explores the therapeutic role of a nootropic herb Bacopa monnieri (BM) in AD-like pathological conditions produced by injecting preformed amyloid-ß42 (Aß42) fibril bilaterally into hippocampus of Wistar rats, and ethanolic extract of BM is orally administered for 4 weeks. Assessment of behavioral changes reveals that BM treatment ameliorates Aß42-induced cognitive impairment and compromised explorative behavior. Supplementation of BM also reduces oxidative stress biomarkers, proinflammatory cytokines, and cholinesterase activity in the AD rats. Additionally, BM treatment restores Bcl-2-associated X protein (Bax)/ B-cell lymphoma 2 (Bcl-2) imbalance, increases neurotrophic factors expression, and prevents neurodegeneration validated by quantifying Nissl-positive hippocampal neurons. Interestingly, BM administration eliminates amyloid plaques in the hippocampal region and normalizes the Aß42-induced increase in phospho-tau and total tau expression. Mechanistic investigations reveal that BM interacts with glycogen synthase kinase (GSK-3ß) and restores Wnt/ß-catenin signaling. CONCLUSION: BM has been used in diet as a nootropic herb for several centuries. This study highlights the anti-Alzheimer activity of BM from the behavioral to the molecular level by modulating mitochondrial dysfunction, and GSK-3ß mediates the Wnt/ß-catenin signaling pathway.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Bacopa , Glicogênio Sintase Quinase 3 beta , Hipocampo , Mitocôndrias , Extratos Vegetais , Ratos Wistar , Via de Sinalização Wnt , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Bacopa/química , Peptídeos beta-Amiloides/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos , Extratos Vegetais/farmacologia , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Fragmentos de Peptídeos , beta Catenina/metabolismo , Modelos Animais de Doenças
5.
Mol Neurobiol ; 2023 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-37957424

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which was proclaimed a pandemic by the World Health Organization (WHO) in March 2020. There is mounting evidence that older patients with multimorbidity are more susceptible to COVID-19 complications than are younger, healthy people. Having neuroinvasive potential, SARS-CoV-2 infection may increase susceptibility toward the development of Parkinson's disease (PD), a progressive neurodegenerative disorder with extensive motor deficits. PD is characterized by the aggregation of α-synuclein in the form of Lewy bodies and the loss of dopaminergic neurons in the dorsal striatum and substantia nigra pars compacta (SNpc) of the nigrostriatal pathway in the brain. Increasing reports suggest that SARS-CoV-2 infection is linked with the worsening of motor and non-motor symptoms with high rates of hospitalization and mortality in PD patients. Common pathological changes in both diseases involve oxidative stress, mitochondrial dysfunction, neuroinflammation, and neurodegeneration. COVID-19 exacerbates the damage ensuing from the dysregulation of those processes, furthering neurological complications, and increasing the severity of PD symptomatology. Phytochemicals have antioxidant, anti-inflammatory, and anti-apoptotic properties. Vitamin C supplementation is found to ameliorate the common pathological changes in both diseases to some extent. This review aims to present the available evidence on the association between COVID-19 and PD, and discusses the therapeutic potential of vitamin C for its better management.

6.
Neuropharmacology ; 237: 109621, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37276957

RESUMO

The role of dopamine (DA)-ergic neurons in ventral tegmental area (VTA) in schizophrenia, depression, hallucinations have been extensively studied. Rapid eye movement sleep (REMS), the closest objective correlate of dream and hallucination, is disrupted during these psychological dysfunctions; however, it was unknown if there is any common neuronal substrate for their regulation. Interactions among locus coeruleus (LC) REM-OFF and pedunculopontine tegmentum (PPT) REM-ON neurons have been reported to regulate REMS in health and diseases. Recently we have reported that PPT neurons modulate VTA and REMS. However, although VTA-DA neurons receive projections from LC and PPT, their role in REMS regulation was unclear. We proposed that the LC and PPT might intermittently modulate VTA-DA neurons and modulate REMS. Male Wistar rats were surgically prepared and electrophysiological wakefulness-sleep-REMS recorded in chronic freely moving condition. We employed RNAi induced downregulation of tyrosine hydroxylase (TH) to evaluate the role of VTA-DA in regulating REMS. We observed that TH-knockdown in VTA decreased REMS in experimental rats, which returned to baseline upon PPT stimulation. Thus, VTA-DA neurons are activated by the REM-ON neurons to modulate REMS, the closest objectively recordable correlate of dreams. In these animals, LC stimulation altered Non-REMS and waking. Based on the findings we have discussed the role of VTA neurochemical circuitry in REMS regulation and their possible implications with REMS-associated dreaming and hallucination in health and diseases.


Assuntos
Locus Cerúleo , Sono REM , Ratos , Masculino , Animais , Locus Cerúleo/fisiologia , Sono REM/fisiologia , Dopamina/fisiologia , Área Tegmentar Ventral , Ratos Wistar , Neurônios/fisiologia , Alucinações
7.
Mol Neurobiol ; 60(8): 4693-4715, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37145378

RESUMO

Parkinson's disease (PD) is a progressive neurodegenerative condition. The pathogenesis of PD is still unknown, and drugs available for PD treatment either have side effects or have suboptimal efficacy. Flavonoids are potent antioxidants having little toxicity with extended use, suggesting they might hold promising therapeutic potential against PD. Vanillin (Van) is a phenolic compound that has exhibited neuroprotective properties in various neurological disorders, including PD. However, the neuroprotective role of Van in PD and its underlying mechanisms are scarce and therefore need more exploration. Here, we evaluated the neuroprotective potential of Van and its associated mechanisms against MPP+/MPTP-induced neuronal loss in differentiated human neuroblastoma (SH-SY5Y) cells and the mouse model of PD. In the present study, Van treatment significantly enhanced the cell viability and alleviated oxidative stress, mitochondrial membrane potential, and apoptosis in MPP+-intoxicated SH-SY5Y cells. Moreover, Van significantly ameliorated the MPP+-induced dysregulations in protein expression of tyrosine hydroxylase (TH) and mRNA expressions of GSK-3ß, PARP1, p53, Bcl-2, Bax, and Caspase-3 genes in SH-SY5Y cells. Similar to our in vitro results, Van significantly alleviated MPTP-induced neurobehavioral dysregulations, oxidative stress, aberrant TH protein expressions, and immunoreactivity in SNpc of mice brains. Treatment of Van also prevented MPTP-mediated loss of TH-positive intrinsic dopaminergic neurons to SNpc and TH-fibers projecting to the striatum of mice. Thus, Van exhibited promising neuroprotective properties in the current study against MPP+/MPTP-intoxicated SH-SY5Y cells and mice, indicating its potential therapeutic properties against PD pathology.


Assuntos
Neuroblastoma , Fármacos Neuroprotetores , Doença de Parkinson , Humanos , Animais , Camundongos , Doença de Parkinson/patologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Fármacos Neuroprotetores/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Linhagem Celular Tumoral , Neuroblastoma/patologia , Apoptose , Neurônios Dopaminérgicos/metabolismo , Camundongos Endogâmicos C57BL
8.
Brain Sci ; 13(2)2023 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-36831815

RESUMO

Parkinson's disease (PD) is the second most common progressive neurodegenerative disorder after Alzheimer's disease. Pathophysiologically, it is characterized by intracytoplasmic aggregates of α-synuclein protein in the Lewy body and loss of dopaminergic neurons from substantia nigra pars compacta and striatum regions of the brain. Although the exact mechanism of neurodegeneration is not fully elucidated, it has been reported that environmental toxins such as MPTP, rotenone, paraquat, and MPP+ induce oxidative stress, which is one of the causative factors for it. To date, there is no complete cure. However, the indispensable role of oxidative stress in mediating PD indicates that antioxidant therapy could be a possible therapeutic strategy against the disease. The deficiency of vitamins has been extensively co-related to PD. Dietary supplementation of vitamins with antioxidant, anti-inflammatory, anti-apoptotic, and free radical scavenging properties could be the potential neuroprotective therapeutic strategy. This review summarizes the studies that evaluated the role of vitamins (A, B, C, D, E, and K) in PD. It will guide future studies in understanding the potential therapeutic role of vitamins in disease pathophysiology and may provide a framework for designing treatment strategies against the disease.

9.
Ageing Res Rev ; 85: 101840, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36603690

RESUMO

Parkinson's disease (PD) is characterized mainly by motor dysfunctions due to the progressive loss of dopaminergic neurons. However, PD patients experience a multitude of debilitating non-motor symptoms, including depression, which may have deleteriously detrimental effects on life. Depression is multifactorial and exhibits a bimodal progression in PD, but its underlying molecular mechanisms are poorly understood. Studies demonstrating the pathophysiology of depression in PD and the specific treatment strategies for depression-like symptoms in PD patients are largely lacking, often underrated, under-recognized and, consequently, inadequately/under-treated. Nevertheless, reports suggest that the incidence of depression is approximately 20-30% of PD patients and may precede the onset of motor symptoms. Diagnosing depression in PD becomes difficult due to the clinical overlap in symptomatology between the two diseases, and the nigrostriatal dysfunction alone is insufficient to explain depressive symptoms in PD. Therefore, the current study provides an overview of the molecular mechanisms underlying the development of depression in PD and new insights into developing current antidepressant strategies to treat depression in PD. This review will identify and understand the molecular pathological mechanisms of depression in PD that will fundamentally help tailoring therapeutic interventions for depressive symptoms in PD.


Assuntos
Doença de Parkinson , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/epidemiologia , Doença de Parkinson/terapia , Depressão/epidemiologia , Depressão/etiologia , Depressão/terapia , Epidemiologia Molecular , Neurônios Dopaminérgicos/patologia
10.
CNS Neurol Disord Drug Targets ; 22(3): 404-416, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-34963438

RESUMO

BACKGROUND: Neurodegenerative diseases, being rapidly increasing disorders and the seventh leading cause of death worldwide, have been a great challenge for researchers, affecting cognition, motor activity and other body functioning due to neurodegeneration. Several neurodegenerative diseases are caused by aggregation of proteins which induce the alteration of neuronal function leading to cell death. These proteins are amyloid-ß peptide, tau, α-synuclein, and mHTT, which cause Alzheimer's disease, Frontotemporal dementia, Corticobasal degeneration, Progressive supranuclear palsy, Parkinson's disease, Multiple system atrophy, Dementia with Lewy-body and Huntington's disease. Currently available treatments only reduce symptoms and increase life sustainability; however, they possess side effects and are ineffective in curing the diseases. OBJECTIVE: Literature survey of neurodegenerative diseases and immunotherapeutic approaches is used to evaluate their pharmacological effects and future endeavours. METHODS: A literature search was performed to find the relevant articles related to neurodegenerative diseases and immunotherapies. Clinical trials data were analysed from clinicaltrial.com. RESULTS: According to the literature study, it was found that researchers have explored the effect of active and passive vaccines generated against amyloid-ß, tau, α-synuclein and mHTT. Few clinical trials have shown severe side effects and terminated, despite that, few of them produced desirable effects for the treatment of AD and PD. CONCLUSION: Several immunotherapeutic trials have shown promising outcomes against amyloid-ß, tau and α-synuclein. In addition, various preclinical studies against mHTT and prion proteins are under scrutinization. These clinical outcomes indicate a promising role of immunotherapies against neurodegenerative diseases.


Assuntos
Doenças Neurodegenerativas , Doença de Parkinson , Humanos , Doenças Neurodegenerativas/terapia , Doenças Neurodegenerativas/metabolismo , alfa-Sinucleína/metabolismo , Proteínas tau , Peptídeos beta-Amiloides , Imunoterapia
11.
Cell Mol Neurobiol ; 43(5): 1885-1904, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36436159

RESUMO

Alcohol consumption is known to cause several brain anomalies. The pathophysiological changes associated with alcohol intoxication are mediated by various factors, most notable being inflammation. Alcohol intoxication may cause inflammation through several molecular mechanisms in multiple organs, including the brain, liver and gut. Alcohol-induced inflammation in the brain and gut are intricately connected. In the gut, alcohol consumption leads to the weakening of the intestinal barrier, resulting in bacteria and bacterial endotoxins permeating into the bloodstream. These bacterial endotoxins can infiltrate other organs, including the brain, where they cause cognitive dysfunction and neuroinflammation. Alcohol can also directly affect the brain by activating immune cells such as microglia, triggering the release of pro-inflammatory cytokines and neuroinflammation. Since alcohol causes the death of neural cells, it has been correlated to an increased risk of neurodegenerative diseases. Besides, alcohol intoxication has also negatively affected neural stem cells, affecting adult neurogenesis and causing hippocampal dysfunctions. This review provides an overview of alcohol-induced brain anomalies and how inflammation plays a crucial mechanistic role in alcohol-associated pathophysiology.


Assuntos
Intoxicação Alcoólica , Encefalopatias , Adulto , Humanos , Doenças Neuroinflamatórias , Encéfalo , Etanol/toxicidade , Inflamação , Neurogênese/fisiologia , Endotoxinas
12.
J Cell Physiol ; 238(2): 306-328, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36502519

RESUMO

Neuroblastoma (NB) is one of the most common heterogeneous extracranial cancers in infancy that arises from neural crest (NC) cells of the sympathetic nervous system. The Wnt signaling pathway, both canonical and noncanonical pathway, is a highly conserved signaling pathway that regulates the development and differentiation of the NC cells during embryogenesis. Reports suggest that aberrant activation of Wnt ligands/receptors in Wnt signaling pathways promote progression and relapse of NB. Wnt signaling pathways regulate NC induction and migration in a similar manner; it regulates proliferation and metastasis of NB. Inhibiting the Wnt signaling pathway or its ligands/receptors induces apoptosis and abrogates proliferation and tumorigenicity in all major types of NB cells. Here, we comprehensively discuss the Wnt signaling pathway and its mechanisms in regulating the development of NC and NB pathogenesis. This review highlights the implications of aberrant Wnt signaling in the context of etiology, progression, and relapse of NB. We have also described emerging strategies for Wnt-based therapies against the progression of NB that will provide new insights into the development of Wnt-based therapeutic strategies for NB.


Assuntos
Neuroblastoma , Via de Sinalização Wnt , Humanos , Diferenciação Celular , Ligantes , Recidiva Local de Neoplasia/patologia , Crista Neural , Neuroblastoma/patologia , Via de Sinalização Wnt/fisiologia , Animais
13.
Neuroscience ; 499: 152-169, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35839924

RESUMO

Aging is a progressive loss of physiological function that increases risk of disease and death. Among the many factors that contribute to human aging, mitochondrial dysfunction has emerged as one of the most prominent features of the aging process. It has been linked to the development of various age-related pathologies, including Parkinson's disease (PD). Mitochondria has a complex quality control system that ensures mitochondrial integrity and function. Perturbations in these mitochondrial mechanisms have long been linked to various age-related neurological disorders. Even though research has shed light on several aspects of the disease pathology, the underlying mechanism of age-related factors responsible for individuals developing this disease is still unknown. This review article aims to discuss the role of mitochondria in the transition from normal brain aging to pathological brain aging, which leads to the progression of PD. We have discussed the emerging evidence on how age-related disruption of mitochondrial quality control mechanisms contributes to the development of PD-related pathophysiology.


Assuntos
Doença de Parkinson , Envelhecimento/fisiologia , Encéfalo/patologia , Humanos , Mitocôndrias/patologia
14.
Mol Neurobiol ; 59(7): 4466-4487, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35575870

RESUMO

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by hyperglycemic conditions. A higher risk of developing Parkinson's disease (PD) in patients with T2DM has become evident in recent years. However, the molecular mechanisms underlying the interplay between T2DM and PD pathogenesis remain unknown. Nevertheless, emerging epidemiological studies have demonstrated many common molecular pathways that play an essential role in regulating normal cellular functioning are independently implicated in the progression and etiopathogenesis of T2DM and PD. This review summarizes some common shared pathophysiological mechanisms, including insulin resistance, inflammation, mitochondrial dysfunction, endoplasmic reticulum stress (ER stress), autophagy, and the ubiquitin-proteasome system (UPS) that independently mediate the onset and etiopathogenesis of T2DM and PD. In this review, we summarize the studies that have reported the relationship between T2DM and PD. This review will provide insights into the common involvement of molecular pathways that may provide alternative treatment strategies for both T2DM and PD.


Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Doença de Parkinson , Diabetes Mellitus Tipo 2/complicações , Humanos , Doença de Parkinson/metabolismo , Complexo de Endopeptidases do Proteassoma , Ubiquitina
15.
Eur J Pharmacol ; 925: 174993, 2022 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-35513015

RESUMO

Evidence supports a strong bidirectional association between depression and Type 2 diabetes mellitus (T2DM). The harmful impact of oxidative stress and chronic inflammation on the development of both disorders is widely accepted. Nuclear factor erythroid 2-related factor 2 (NRF2) is a pertinent target in disease management owing to its reputation as the master regulator of antioxidant responses. NRF2 influences the expression of various cytoprotective phase 2 antioxidant genes, which is hampered in both depression and T2DM. Through interaction and crosstalk with several signaling pathways, NRF2 endeavors to contain the widespread oxidative damage and persistent inflammation involved in the pathophysiology of depression and T2DM. NRF2 promotes the neuroprotective and insulin-sensitizing properties of its upstream and downstream targets, thereby interrupting and preventing disease advancement. Standard antidepressant and antidiabetic drugs may be powerful against these disorders, but unfortunately, they come bearing distressing side effects. Therefore, exploiting the therapeutic potential of NRF2 activators presents an exciting opportunity to manage such bidirectional and comorbid conditions.


Assuntos
Diabetes Mellitus Tipo 2 , Fator 2 Relacionado a NF-E2 , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Depressão/tratamento farmacológico , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Inflamação , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo
16.
Mech Ageing Dev ; 204: 111675, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35430158

RESUMO

Aging is inevitable. Along with reduced ability to maintain the homeostasis of various biological processes, aging gradually deteriorates overall health. Extensive research on the aging brain has identified cellular senescence as a critical risk factor of neurodegeneration and cognitive decline. Associations of cellular senescence with neurodegenerative diseases like Alzheimer's disease, Down syndrome, Parkinson's disease, and multiple sclerosis are evident in an extensive body of literature generated over decades of research on aging. Cellular senescence triggers neurodegeneration via a complex interplay of mechanisms including neuroinflammation, mitochondrial dysfunction, oxidative stress burden, deranged protein homeostasis, and compromised nuclear and blood-brain-barrier integrity. Thus, cellular senescence can serve as a primary therapeutic target for various neurodegenerative diseases. This review summarizes the concept of cellular senescence, its role in the aging brain, and how it mediates neurodegeneration in several neurodegenerative disorders. Further, we have also highlighted senolytic therapeutics discovered and employed to ameliorate cellular senescence-associated degenerative diseases. This review can aid in providing directions for repurposing senolytic compounds and finding more therapeutic strategies targeting cellular senescence for the management and treatment of neurodegenerative diseases.


Assuntos
Doenças Neurodegenerativas , Envelhecimento , Encéfalo/metabolismo , Senescência Celular , Humanos , Doenças Neurodegenerativas/metabolismo , Senoterapia
17.
Neuropharmacology ; 201: 108831, 2021 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-34655599

RESUMO

Parkinson's disease (PD), a common neurodegenerative disease is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. The cause of dopaminergic loss in PD remains unknown for a long time, however, recent reports suggest oxidative stress plays a key role in the pathogenesis of PD. Paraquat (PQ), a widely used herbicide is an oxidative stress inducer that has been implicated as a potential risk factor for the development of PD. Flavonoids are naturally occurring polyphenolic compounds that display a variety of therapeutic properties against oxidative stress. Naringenin (NAR), a natural flavonoid, exhibits neuroprotection against PD-related pathology. However, studies on its neuroprotective role and the underlying mechanisms are scarce, therefore the present study explored the potential neuroprotective role of NAR in PQ-induced parkinsonism in SH-SY5Y cells and rat model. The effect of NAR on PQ-induced cellular toxicity was determined by measuring cell viability, oxidative stress, ATP levels and the same effect was determined by assessing behavioral, biochemical, immunohistochemical, qRT-PCR and Western blot in rat model. NAR treatment in SH-SY5Y cells resulted in increased cell viability, reduced oxidative stress, elevated mitochondrial membrane potential, and higher cellular ATP levels. In rats, NAR treatment resulted in significant neuroprotection against PQ-induced behavioral deficits, oxidative stress, mitochondrial dysfunction, and astrocytosis. NAR treatment significantly modulated PQ-induced mRNA expressions of DRD2, DAT, LRRK2, SNCA, ß-catenin, caspase-3, BDNF genes. NAR treatment increased TH protein expression and modulated its immunoreactivity in rat striatum. Also, GFAP decreased in response to NAR treatment. So, in the present study, NAR exhibits neuroprotection against PQ-induced neurotoxicity and neurodegeneration indicating its novel therapeutic potential against PD.


Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Flavanonas/farmacologia , Herbicidas/efeitos adversos , Fármacos Neuroprotetores , Paraquat/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/patologia , Trifosfato de Adenosina/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Humanos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Substância Negra/citologia , Substância Negra/patologia
18.
Neurochem Res ; 46(11): 3059-3074, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34357519

RESUMO

Paraquat (PQ), an environmental neurotoxicant, causes acute fatal poisoning upon accidental or intentional ingestion (suicidal cases) worldwide. To date, an effective remedy for PQ toxicity is not available. In this study, we have evaluated the therapeutic efficacy of Bacopaside-I (BS-I), an active compound found in the plant extract of Bacopa monnieri (Brahmi), against acute PQ intoxication using zebrafish as a model organism. Adult zebrafish were injected with a dose of either 30 mg/kg or 50 mg/kg PQ. PQ-intoxicated zebrafish showed an increased rate of mortality and oxidative imbalance in their brain. Also, the proliferation of neural cells in the adult zebrafish brain was inhibited. However, when BS-I pretreated zebrafish were intoxicated with PQ, the toxic effects of PQ were ameliorated. PQ treatment also affected the expression of particular genes concerned with the apoptosis and dopamine signaling, which was not altered by BS-I administration. Our results highlight the efficiency of BS-I as a novel therapeutic agent for PQ intoxication. It further compels us to search and evaluate the molecular mechanisms targeted by BS-I to develop a potent therapy for acute PQ intoxication.


Assuntos
Bacopa , Encéfalo/efeitos dos fármacos , Herbicidas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Paraquat/toxicidade , Saponinas/farmacologia , Triterpenos/farmacologia , Fatores Etários , Animais , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Feminino , Masculino , Estresse Oxidativo/fisiologia , Peixe-Zebra
19.
Mol Biol Rep ; 48(6): 5099-5108, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34165768

RESUMO

Recent findings suggest a significant role of the brain-derived neurotrophic factor (BDNF) as a mediator of brain regeneration following a stab injury in zebrafish. Since BDNF has been implicated in many physiological processes, we hypothesized that these processes are affected by brain injury in zebrafish. Hence, we examined the impact of stab injury on oxidative stress and apoptosis in the adult zebrafish brain. Stab wound injury (SWI) was induced in the right telencephalic hemisphere of the adult zebrafish brain and examined at different time points. The biochemical variables of oxidative stress insult and transcript levels of antioxidant genes were assessed to reflect upon the oxidative stress levels in the brain. Immunohistochemistry was performed to detect the levels of early apoptotic marker protein cleaved caspase-3, and the transcript levels of pro-apoptotic and anti-apoptotic genes were examined to determine the effect of SWI on apoptosis. The activity of antioxidant enzymes, the level of lipid peroxidation (LPO) and reduced glutathione (GSH) were significantly increased in the injured fish brain. SWI also enhanced the expression of cleaved caspase-3 protein and apoptosis-related gene transcripts. Our results indicate induction of oxidative stress and apoptosis in the telencephalon of adult zebrafish brain by SWI. These findings contribute to the overall understanding of the pathophysiology of traumatic brain injury and adult neurogenesis in the zebrafish model and raise new questions about the compensatory physiological mechanisms in response to traumatic brain injury in the adult zebrafish brain.


Assuntos
Lesões Encefálicas/fisiopatologia , Regeneração do Cérebro/fisiologia , Estresse Oxidativo/fisiologia , Animais , Apoptose/genética , Encéfalo/metabolismo , Lesões Encefálicas/genética , Lesões Encefálicas/metabolismo , Lesões Encefálicas Traumáticas , Regeneração do Cérebro/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Modelos Animais de Doenças , Regeneração Nervosa/fisiologia , Neurogênese/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Telencéfalo/lesões , Telencéfalo/metabolismo , Telencéfalo/fisiopatologia , Ferimentos Perfurantes/metabolismo , Ferimentos Perfurantes/fisiopatologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
20.
Eur J Neurosci ; 53(8): 2870-2900, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33529409

RESUMO

Diabetes increases the likelihood of developing depression and vice versa. Research on this bidirectional association has somewhat managed to delineate the interplay among implicated physiological processes. Still, further exploration is required in this context. This review addresses the comorbidity by investigating suspected common pathophysiological mechanisms. One such factor is psychological stress which disturbs the hypothalamic-pituitary-adrenal axis causing hormonal imbalance. This includes elevated cortisol levels, a common biomarker of both depression and diabetes. Disrupted insulin signaling drives the hampered neurotransmission of serotonin, dopamine, and norepinephrine. Also, adipokine hormones such as adiponectin, leptin, and resistin and the orexigenic hormone, ghrelin, are involved in both depression and T2DM. This disarray further interferes with physiological processes encompassing sleep, the gut-brain axis, metabolism, and mood stability. Behavioral coping mechanisms, such as unhealthy eating, mediate disturbed glucose homeostasis, and neuroinflammation. This is intricately linked to oxidative stress, redox imbalance, and mitochondrial dysfunction. However, interventions such as psychotherapy, physical exercise, fecal microbiota transplantation, and insulin-sensitizing agents can help to manage the distressing condition. The possibility of glucagon-like peptide 1 possessing a therapeutic role has also been discussed. Nonetheless, there stands an urgent need for unraveling new correlating targets and biological markers for efficient treatment.


Assuntos
Diabetes Mellitus Tipo 2 , Microbiota , Depressão/terapia , Diabetes Mellitus Tipo 2/terapia , Exercício Físico , Transplante de Microbiota Fecal , Humanos , Sistema Hipotálamo-Hipofisário , Sistema Hipófise-Suprarrenal , Psicoterapia
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