RESUMO
SARS-CoV-2 infection causes asymptomatic to severe human respiratory diseases. Vaccinations are effective only to a certain extent, and the disease recurs with milder symptoms even after booster doses. Hence, we hypothesize that antiviral therapy in conjunction with vaccination is the need of the hour for containing the disease. SARS-CoV-2 enters the host cell through interaction between viral spike (S) protein and human Angiotensin II converting enzyme2 (ACE2). So, any S-protein neutralizing molecule could be a potential antiviral moiety. The interaction-interface architecture indicates that cationic peptides effectively bind to anionic interface residues of S protein-receptor binding domain (S-RBD). Subsequently, we adopted molecular docking and simulation approaches to examine the binding affinity of cationic human α and ß defensins, HNP1 and HBD2 with S-RBD. We observed strong hydrogen bonds, electrostatic, salt bridge, and hydrophobic interactions between these defensins and S-RBD with binding energy (BE) of -10.7 kcal/mol. Interestingly, defensins from Zea mays (ZmD32), Solanum lycopersicum (TPP3), and Sorghum bicolor (DEF1_SORBI) exhibited approximately similar BE of -11.1 kcal/mol, -11.9 kcal/mol, and -12.6 kcal/mol respectively, comparable to ACE2 (BE= -11.9 kcal/mol). Molecular dynamics simulation of S-RBD complexes formed with HBD2, ZmD32 and TPP3, showed stable associations for 100 ns. Results of in-silico studies demonstrated higher binding affinity of more positively-charged peptides with S-RBD, suggesting the potential of plant defensins to block ACE2 binding of S-RBD. These results warrant experimental validation. However these findings indicate the usefulness of plant defensin homologues as neutralizing antiviral agents for use as ideal prophylactic and therapeutic drugs for COVID-19.Communicated by Ramaswamy H. Sarma.
Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Enzima de Conversão de Angiotensina 2 , Simulação de Acoplamento Molecular , Antivirais , Simulação de Dinâmica Molecular , DefensinasRESUMO
Objectives: Parkinson's disease (PD) patients have suffered during the coronavirus disease 2019 pandemic, with worsening of both motor and nonmotor symptoms. We conducted this study to evaluate the quality of life (QoL) and concerns of PD patients and their caregivers. Methods: The study was conducted in mixed method, where the baseline data was taken by face-to-face interview during the unlock phase of December 2020 to March 2021, when there was no lockdown. This included demography, Hoehn and Yahr (HY) stage, Parkinson's Disease Questionnaire-8 (PDQ-8), and Parkinson's Disease Questionnaire for Carer (PDQ-Carer). During the second wave of COVID-19 (April-June 2021), telephonic interview was conducted using Depression, Anxiety Stress Scale- 21 Items (DASS-21), PDQ-8, PDQ-Carer, and open-ended questions regarding their concerns. Results: Compared with the baseline data, PDQ-8 and PDQ-Carer scores showed significant worsening during the second wave. DASS-21 scores had significant correlation with PDQ-Carer and PDQ-8 scores. Female patients reported poorer QoL. Caregivers of non-vaccinated patients had worse PDQ-Carer Strain scores. There was no significant association between worsening of motor symptoms and PDQ-8 and PDQ-Carer scores. More than 80% patients and 70% caregivers reported anxiety and depression. Their concerns were regarding difficulties due to social isolation, restriction of activity, and financial constraints. Additionally, there were worries about patient care, vaccination, and recurrence of the wave. Conclusions: The QoL of both patients and their caregivers were affected by the pandemic. A significant proportion had anxiety and depression, and this correlated with QoL. There were some important concerns on various aspects of the pandemic.
RESUMO
In this Special Issue on "Nutraceuticals: Molecular and Functional Insights into how Natural Products Nourish the Brain", the editors bring together contributions from experts in nutraceutical research to provide a contemporary overview of how select chemically identified molecules from natural products can beneficially affect brain function at the molecular level. Other contributions address the holistic benefit of herbal medicines and their multi-targeted actions, which improve brain function in diverse cellular and animal models of brain injury. Not only are new targets for nutraceuticals reported, but their benefits on neurobehavioural problems are elucidated in conditions as diverse as obesity and menopause. Inflammation in neuropathologies, including Alzheimer's disease (AD), remains a huge focus and diverse nutraceuticals demonstrate therapeutic applicability via glial-mediated actions. While contrary actions should be borne in mind in the search for novel neurotherapeutics, the great promise offered by herbal medicines and their newly identified active principles offers unique options for the management of diverse neurological and psychiatric conditions.
Assuntos
Produtos Biológicos/administração & dosagem , Encéfalo/efeitos dos fármacos , Suplementos Nutricionais , Animais , Produtos Biológicos/efeitos adversos , Produtos Biológicos/metabolismo , Encéfalo/metabolismo , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/metabolismo , Suplementos Nutricionais/efeitos adversos , Humanos , Plantas Medicinais/efeitos adversosRESUMO
Alzheimer's disease (AD) is the most common neurodegenerative disease, and its incidence is increasing worldwide with increased lifespan. Currently, there is no effective treatment to cure or prevent the progression of AD, which indicates the need to develop novel therapeutic targets and agents. Sirtuins, especially SIRT3, a mitochondrial deacetylase, are NAD-dependent histone deacetylases involved in aging and longevity. Accumulating evidence indicates that SIRT3 dysfunction is strongly associated with pathologies of AD, hence, therapeutic modulation of SIRT3 activity may be a novel application to ameliorate the pathologies of AD. Natural products commonly used in traditional medicine have wide utility and appear to have therapeutic benefits for the treatment of neurodegenerative diseases such as AD. The present review summarizes the currently available natural SIRT3 activators and their potentially neuroprotective molecular mechanisms of action that make them a promising agent in the treatment and management of neurodegenerative diseases such as AD.
Assuntos
Doença de Alzheimer/enzimologia , Suplementos Nutricionais , Sistemas de Liberação de Medicamentos/métodos , Inibidores Enzimáticos/administração & dosagem , Neuroproteção/fisiologia , Sirtuína 3/metabolismo , Envelhecimento/efeitos dos fármacos , Envelhecimento/metabolismo , Doença de Alzheimer/dietoterapia , Doença de Alzheimer/tratamento farmacológico , Animais , Compostos de Bifenilo/administração & dosagem , Sistemas de Liberação de Medicamentos/tendências , Glucosídeos/administração & dosagem , Humanos , Hidrazinas/administração & dosagem , Indazóis/administração & dosagem , Lignanas/administração & dosagem , Neuroproteção/efeitos dos fármacos , Fenóis/administração & dosagem , Sirtuína 3/antagonistas & inibidoresRESUMO
Kessler et al. in this current issue have attempted to discern biomarker(s) for spinal muscular atrophy (SMA) by assessing alterations in cerebrospinal fluid (CSF) proteomics profile. Recently, antisense oligonucleotide (nusinersen) therapy is shown to mitigate pathologies and provide behavioral improvements in patients. This Editorial highlights the study by Kessler et al on the proteomics of CSF from adult and young patients prior to, and 10 months after nusinersen intrathecal therapy. Although the study by Kessler et al. suffers from small sample size and mixed results that deterred a strong conclusion, yet is a strong case-control study that is contemporary and important to the patients, clinicians and care-takers alike. Since identifying biomarker and characterizing the pathology in SMA are imminent necessity to advance this promising therapy, the high-throughput CSF proteomics data prior and after nusinersen therapy provide possible biomarkers that may help in identification of positive responders, the disease course, efficacy of treatment, and more accurate prognosis.
Assuntos
Atrofia Muscular Espinal/líquido cefalorraquidiano , Atrofia Muscular Espinal/tratamento farmacológico , Oligonucleotídeos/uso terapêutico , Proteômica/métodos , Biomarcadores/líquido cefalorraquidiano , Humanos , Atrofia Muscular Espinal/genética , Proteômica/tendênciasRESUMO
We have recently demonstrated neuroprotective abilities of nimodipine, an L-type voltage dependent calcium channel (VDCC) blocker in cellular and animal models of Parkinson's disease (PD). To understand the calcium regulatory mechanisms in the disease pathogenesis, the present study examined calcium regulatory proteins calbindin and calpain mRNA and protein levels employing quantitative PCR and western blot in 1-methyl-4-phenyl pyridinium ion (MPP+)-treated SH-SY5Y cell lines and in the striatum of mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). mRNA and protein levels of calbindin were lower, while that of calpain were higher in MPP+-treated SH-SY5Y cells and MPTP-treated mouse striatum as compared to their respective controls. Nimodipine pretreatment significantly attenuated these effects in the parkinsonian neurotoxin-treated SH-SY5Y cell line and in the mouse striatum. The activities of the apoptotic mediator, caspase-3 and calpain were increased in the neurotoxin-treated groups as compared to their respective controls, which was ameliorated by nimodipine pretreatment. These results suggest that parkinsonian neurotoxin-mediated dopaminergic neuronal death might involve defects in calcium regulatory proteins that control intracellular calcium homeostasis, and these could be corrected by inhibiting L-type VDCC activity. These findings support the notion that hypertensive patients who are on long-term intake of dihydropyridine have reduced risk for PD.
Assuntos
Calbindinas/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Calpaína/metabolismo , Intoxicação por MPTP/metabolismo , Nimodipina/farmacologia , Transtornos Parkinsonianos/metabolismo , Animais , Calbindinas/efeitos dos fármacos , Calpaína/efeitos dos fármacos , Linhagem Celular , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fármacos Neuroprotetores/farmacologiaRESUMO
Platelet hyperserotonemia in a subset of Autism Spectrum Disorder (ASD) probands, efficacy of selective serotonin reuptake inhibitors (SSRIs) in reducing behavioral deficits and gender-bias in normal serotonin (5-hydroxy tryptamine or 5-HT) synthesis suggest disruption in stringent regulation of serotonin metabolism in ASD. Therefore, we investigated the changes in 5-HT and 5-hydroxy indole acetic acid (5-HIAA) in ASD probands to assess its effect on the behavior of male and female probands. ASD cases (n = 215) were examined using childhood autism rating scale (CARS). Platelet 5-HT (104 cases and 26 controls) and platelet/plasma 5-HIAA (73 cases and 17 controls) were estimated using high performance liquid chromatography coupled with electrochemical detector (HPLC-ECD). In male probands, we observed increase in platelet 5-HT content in association with increase in the score for adaptive responses and increase in platelet 5-HIAA levels with concomitant decline in the score for intellectual response. Age did not influence the neurochemical parameters, but imitation, listening responses and nonverbal communication scores decreased with age. Conversely in female probands, plasma 5-HIAA level significantly attenuated with age, when platelet 5-HT content remained unchanged. Interestingly, platelet/plasma 5-HT and plasma 5-HIAA were higher in female controls. Female probands displayed severe autism-associated behaviors. Overall results indicate gender-bias in 5-HT and 5-HIAA regulation, which probably increases the threshold level of ASD phenotypes in the females, thereby affecting ASD prevalence in a sex-specific manner.
RESUMO
Parkinson's disease (PD) has no known cure; available therapies are only capable of offering temporary, symptomatic relief to the patients. Varied therapeutic strategies that are clinically used for PD are pharmacological therapies including dopamine replacement therapies (with or without adjuvant), postsynaptic dopamine receptor stimulation, dopamine catabolism inhibitors and also anticholinergics. Surgical therapies like deep brain stimulation and ablative surgical techniques are also employed. Phosphodiesterases (PDEs) are enzymes that degrade the phosphodiester bond in the second messenger molecules, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). A number of PDE families are highly expressed in the striatum including PDE1-4, PDE7, PDE9 and PDE10. There are growing evidences to suggest that these enzymes play a critical role in modulating cAMP-mediated dopamine signalling at the postsynaptic region. Therefore, it is clear that PDEs, given the broad range of subtypes and their varied tissue- and region-specific distributions, will be able to provide a range of possibilities as drug targets. There is no phosphodiesterase inhibitor currently approved for use against PD. The development of small molecule inhibitors against cyclic nucleotide PDE is a particularly hot area of investigation, and a lot of research and development is geared in this direction with major players in the pharmaceutical industry investing heavily in developing such potential drug entities. This review, while critically assessing the existing body of literature on brain PDEs with particular interest in the striatum in the context of motor function regulation, indicates it is certainly likely that PDE inhibitors could be developed as therapeutic agents against PD.
Assuntos
Doença de Parkinson/tratamento farmacológico , Inibidores de Fosfodiesterase/uso terapêutico , Animais , Humanos , Terapia de Alvo Molecular , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismoRESUMO
Since substantia nigra (SN) and ventral tegmental area (VTA) dopaminergic neurons are, respectively, susceptible or largely unaffected in Parkinson's disease (PD), we searched for protein(s) that regulates this differential sensitivity. Differentially, expressed proteins in SN and VTA were investigated employing two-directional gel electrophoresis- matrix-assisted laser desorption ionization time of flight (MALDI-TOF-TOF) analyses. Prohibitin, which is involved in mitochondrial integrity, was validated using immunoblot, qRT-PCR, and immunohistochemistry in normal mice as well as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-model, PD postmortem human brains, and PD cybrids. In prohibitin over-expression, differentiated SH-SY5Y neurons were investigated for their susceptibility to PD neurotoxin, 1-methyl-4-phenyl-pyridnium (MPP+). Prohibitin, Hsc73, and Cu-Zn superoxide dismutase (Cu-Zn SOD) were highly expressed in VTA, whereas heat shock protein A8 (HSPA8) and 14-3-3ζ/δ were 2-fold more in SN. Prohibitin level was transiently increased in SN but unaltered in VTA on the third day of MPTP-induced mice, whereas in PD human brains, prohibitin was depleted in both these regions. Parallel to mouse SN, an enhanced prohibitin expression was found in human PD cybrids. In MPP+-induced cellular model of PD, reduction in prohibitin level was found to be associated with a loss in its binding with Ndufs3, a mitochondrial complex I protein partner. Prohibitin over-expression resisted MPP+-induced neuronal death by restoring mitochondrial membrane potential, preventing reactive oxygen species generation and cytochrome c release into cytosol. These protective phenomena exerted by prohibitin over-expression altogether hinder caspase 3 activation induced by MPP+. These results imply that prohibitin is an important negotiator protein that regulates dopaminergic cell death in SN and their protection in VTA in PD.
Assuntos
Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Proteínas Repressoras/metabolismo , Substância Negra/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Adenoviridae/metabolismo , Idoso , Animais , Caspase 3/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Citocromos c/metabolismo , Eletroforese em Gel Bidimensional , Feminino , Humanos , Células Híbridas , Masculino , Potencial da Membrana Mitocondrial , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Mudanças Depois da Morte , Proibitinas , Proteômica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Repressoras/genética , Área Tegmentar Ventral/metabolismo , Área Tegmentar Ventral/patologiaRESUMO
BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is an etiologically complex childhood onset neurobehavioral disorder characterized by age-inappropriate inattention, hyperactivity, and impulsivity. Symptom severity varies widely and boys are diagnosed more frequently than girls. ADHD probands were reported to have abnormal transmissions of dopamine, serotonin, and/or noradrenaline. Monoamine oxidase A (MAOA) and B (MAOB), mitochondrial outer membrane bound two isoenzymes, mediate degradation of these neurotransmitters and thus regulating their circulating levels. Case-control analyses in different populations, including Indians, suggested involvement of MAOA and MAOB genes in the etiology of ADHD. Due to high heritability rate of ADHD, we tested familial transmission of MAOA and MAOB variants to ADHD probands in 190 nuclear families having ADHD probands from Indo-Caucasoid ethnicity. METHODS: Subjects were recruited following the Diagnostic and Statistical Manual of Mental Disorders-4th edition (DSM-IV). Appropriate scales were used for measuring the behavioral traits in probands. Genotyping was performed through PCR-based amplification of target sites followed by DNA-sequencing and/or gel-electrophoresis. Data obtained were analyzed by family based statistical methods. RESULTS: Out of 58 variants present in the analyzed sites only 15 were found to be polymorphic (30 bp-uVNTR, rs5906883, rs1465107, rs1465108, rs5905809, rs5906957, rs6323, rs1137070 from MAOA and rs4824562, rs56220155, rs2283728, rs2283727, rs3027441, rs6324, rs3027440 from MAOB). Statistically significant maternal transmission of alleles to male probands was observed for MAOA rs5905809 'G' (p = 0.04), rs5906957 'A' (p = 0.04), rs6323 'G' (p = 0.0001) and MAOB rs56220155 'A' (p = 0.002), rs2283728 'C' (p = 0.0008), rs2283727 'C' (p = 0.0008), rs3027441 'T' (p = 0.003), rs6324 'C' (p = 0.003), rs3027440 'T' (p = 0.0002). Significantly preferential maternal transmissions of different haplotype combinations to male probands were also noticed (p < 0.05), while female probands did not reveal such transmission bias. Behavioral traits of male probands exhibited significant association with gene variants. Age of the mother at pregnancy also revealed association with risk variants of male probands. CONCLUSIONS: It may be inferred that the MAOA and MAOB variants may contribute to the etiology of ADHD in the Indo-Caucasoid population and could be responsible for higher occurrence of ADHD in the boys.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/genética , Predisposição Genética para Doença , Monoaminoxidase/genética , Comportamento Problema/psicologia , Alelos , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Técnicas de Genotipagem , Haplótipos , Humanos , Masculino , Projetos Piloto , População Branca/genéticaRESUMO
BACKGROUND: Pathophysiology of attention-deficit hyperactivity disorder (ADHD) is not known, and therefore the present study investigated mitochondrial defects, if any in cybrids created from patients and control population. METHODS: To investigate mitochondrial pathology in ADHD, cybrids cell lines were created from ADHD probands and controls by fusing their platelets with ρ0-cells prepared from SH-SY5Y neuroblastoma cell line. Cellular respiration, oxidative stress, mitochondrial membrane potential and morphology were evaluated employing oxygraph, mitochondria-specific fluorescence staining and evaluation by FACS, and immunocytochemistry. HPLC-electrochemical detection, quantitative RT-PCR and Blue Native PAGE were employed respectively for assays of serotonin, mitochondrial ATPase 6/8 subunits levels and complex V activity. RESULTS: Significantly low cellular and mitochondrial respiration, ATPase6/8 transcripts levels, mitochondrial complex V activity and loss of mitochondrial membrane potential and elevated oxidative stress were observed in ADHD cybrids. Expression of monoamine oxidizing mitochondrial enzymes, MAO-A and MAO-B levels remained unaffected. Two-fold increase in serotonin level was noted in differentiated cybrid-neurons. CONCLUSIONS: Since cybrids are shown to replicate mitochondrial defects seen in post-mortem brains, these observed defects in ADHD cybrids strongly suggest mitochondrial pathology in this disorder. GENERAL SIGNIFICANCE: Mitochondrial defects are detected in ADHD cybrids created from patients' platelets, implying bioenergetics crisis in the mitochondria could be a contributory factor for ADHD pathology and/or phenotypes.
RESUMO
Serotonergic system participates in various developmental processes and modulation of behaviour. Autism Spectrum Disorder (ASD) is characterized by a range of behavioral symptoms scaling from mild to severe. Abnormal 5-HT synthesis and signalling, platelet hyperserotonemia and amelioration of repetitive behaviours by SSRI are some of the key findings, which reinforced the hypothesis that serotonergic genes might act as ASD susceptible genes. Therefore, genes encoding monoamine oxidases A/B (MAOA/MAOB) received special attention as these genes are located on the X-chromosome and the gene products are responsible for 5-HT degradation. In the present study, we conducted population-based association analysis of eight markers of MAOB with ASD in a study cohort of 203 cases and 236 controls form India and examined its effect on platelet 5-HT content and behaviour. Gender-specific changes were observed for the contrasting LD between pair of markers among cases and controls. Case-control analysis demonstrated over-distribution of major C allele of rs2283728 and rs2283727 in male and female ASD cases respectively. Haplotypic distribution and interaction among markers showed more robust effect in male cases. Interestingly, male ASD cases displayed higher platelet 5-HT content in comparison to the respective controls. Quantitative trait analysis revealed significant correlation of genetic variants and haplotypes of MAOB markers, rs1799836 and rs6324 with increased platelet 5-HT level and CARS scores for specific behavioral symptoms respectively in males. This study suggests that MAOB increases ASD risk in males, possibly through its sex-specific regulatory effect on 5-HT metabolism and behavior.
Assuntos
Transtorno do Espectro Autista , Predisposição Genética para Doença/genética , Transtornos Mentais/etiologia , Monoaminoxidase/genética , Polimorfismo de Nucleotídeo Único/genética , Serotonina/sangue , Adolescente , Adulto , Transtorno do Espectro Autista/sangue , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Índia , Masculino , Escalas de Graduação Psiquiátrica , Fatores Sexuais , Adulto JovemRESUMO
Parkinson's disease (PD), the most common progressive neurodegenerative movement disorder, results from loss of dopaminergic neurons of substantia nigra pars compacta. These neurons exhibit Cav1.3 channel-dependent pacemaking activity. Epidemiological studies suggest reduced risk for PD in population under long-term antihypertensive therapy with L-type calcium channel antagonists. These prompted us to investigate nimodipine, an L-type calcium channel blocker for neuroprotective effect in cellular and animal models of PD. Nimodipine (0.1-10 µM) significantly attenuated 1-methyl-4-phenyl pyridinium ion-induced loss in mitochondrial morphology, mitochondrial membrane potential and increases in intracellular calcium levels in SH-SY5Y neuroblastoma cell line as measured respectively employing Mitotracker green staining, TMRM, and Fura-2 fluorescence, but only a feeble neuroprotective effect was observed in MTT assay. Nimodipine dose-dependently reduced 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian syndromes (akinesia and catalepsy) and loss in swimming ability in Balb/c mice. It attenuated MPTP-induced loss of dopaminergic tyrosine hydroxylase positive neurons in substantia nigra, improved mitochondrial oxygen consumption and inhibited reactive oxygen species production in the striatal mitochondria measured using dichlorodihydrofluorescein fluorescence, but failed to block striatal dopamine depletion. These results point to an involvement of L-type calcium channels in MPTP-induced dopaminergic neuronal death in experimental parkinsonism and more importantly provide evidences for nimodipine to improve mitochondrial integrity and function.
Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Bloqueadores dos Canais de Cálcio/uso terapêutico , Mitocôndrias/metabolismo , Nimodipina/uso terapêutico , Doença de Parkinson Secundária/metabolismo , Doença de Parkinson Secundária/prevenção & controle , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/fisiologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Humanos , Intoxicação por MPTP/induzido quimicamente , Intoxicação por MPTP/metabolismo , Intoxicação por MPTP/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mitocôndrias/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Nimodipina/farmacologia , Doença de Parkinson Secundária/induzido quimicamente , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is characterized by symptoms of inattention, excessive motor activity and impulsivity detected mostly during childhood. These traits are known to be controlled by monoamine neurotransmitters, chiefly dopamine, serotonin and norepinephrine. Monoamine oxidase A (MAOA) and B (MAOB), two isoenzymes bound to the outer membrane of mitochondria, are involved in the degradation of monoamines and were explored for association with ADHD in different ethnic groups. In the present study, few exonic as well as intronic MAOB variants were analyzed in ADHD probands (N = 150) and ethnically matched controls (N = 150) recruited following the Diagnostic and Statistical Manual for Mental Disorders-4(th) edition (DSM-IV). Appropriate scales were used for measuring the behavioural attributes. Gene variants were analyzed by amplification of target sites followed by DNA sequencing and data obtained were analyzed by population based statistical methods. RESULTS: Out of 34 variants present in the analyzed sites, only seven functional variants, rs4824562, rs56220155, rs2283728, rs2283727, rs3027441, rs6324 and rs3027440, were found to be polymorphic. rs2283728 'C' (P = 3.45e-006) and rs3027440 'T' (P = 0.02) alleles showed higher frequencies in ADHD probands as compared to controls. rs56220155 'A' (P = 0.04) allele and 'GA' (P = 0.04) genotype showed higher frequencies in the male and female ADHD probands respectively as compared to sex-matched controls. Analysis of pairwise linkage disequilibrium revealed striking differences between probands and controls. Haplotype analysis revealed significantly higher occurrence of different haplotypes in the ADHD probands while some haplotypes were detected in the controls only. Higher scores for conduct problems were found to be associated with rs56220155 'A' (P = 0.05) allele in the male ADHD probands. Multifactor dimensionality reduction analysis showed independent as well as interactive effects of polymorphic variants which were more robust in the male probands. CONCLUSIONS: Since all the polymorphic variants analyzed were functional, it may be inferred that MAOB gene variants are contributing to the etiology of ADHD in the Indo-Caucasoid population from eastern India which merits further in depth analysis.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/enzimologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Variação Genética , Monoaminoxidase/genética , População Branca/genética , Adolescente , Criança , Pré-Escolar , Feminino , Frequência do Gene , Genótipo , Humanos , Índia , Desequilíbrio de Ligação , Masculino , FenótipoRESUMO
The research on aging and age-related diseases, especially the neurodegenerative diseases, is on the fast track. However, the results have so far not been translated to actual benefit for the patients in terms of treatment or diagnosis of age-related degenerative diseases including those of the CNS. As far as the prevention of the cognitive decline during non-pathological aging is concerned, there is nothing much to offer other than calorie restriction and physical exercise. Needless to say, the benefits are not up to our expectations. However, over the years at the experimental level it has been possible to identify several cellular and molecular mechanisms that are intricately associated with aging in general and neurodegenerative diseases in particular. These include oxidative stress and altered redox-signaling, mitochondrial dysfunction, inflammation, proteotoxicity and altered gene expressions. These inter-dependent pathways mediate cellular senescence and often culminate in programmed cell death like apoptosis and autophagy, and in the context of brain these changes are manifested clinically as cognitive decline and pathologically as neurodegeneration. This special issue provides the readers with glimpses of this complex scenario from different angles primarily in the context of brain and also attempts to identify the potential drug targets against neurodegenerative diseases.
RESUMO
In this Special Issue on "Nutraceuticals: Molecular and Functional Insights into how Natural Products Nourish the Brain", the editors bring together contributions from experts in nutraceutical research to provide a contemporary overview of how select chemically identified molecules can beneficially affect brain function at the molecular level. Other contributions address key emergent issues such as bioavailability, formulation, blood brain permeability, neuronal health and inflammation that impact upon how nutraceuticals ultimately leverage the brain to function better. Whilst nutraceutical is used as marketing term, it has no regulatory definition, and there is a continuing need for licensing authorities to ensure that adequate guidelines exist pertinent to the safety to guide consumers internationally. In terms of the benefit of nutraceuticals is it clear that some naturally occurring molecules can be advantageous to both the young and aged brain, and that they have actions that ultimately can be directed to aid either in the improvement of cognition or in the management of debilitating neurodegenerative and neuropsychiatric conditions.
Assuntos
Produtos Biológicos/administração & dosagem , Encéfalo/efeitos dos fármacos , Dietoterapia/tendências , Suplementos Nutricionais , Envelhecimento/efeitos dos fármacos , Envelhecimento/fisiologia , Animais , Encéfalo/fisiologia , Dietoterapia/métodos , Flavonoides/administração & dosagem , Humanos , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/dietoterapia , Doenças Neurodegenerativas/tratamento farmacológicoRESUMO
The major neurodegenerative movement disorder Parkinson's disease (PD) is characterized by rest-tremor, akinesia, rigidity and inability to initiate movements. PD syndromes result from excessive loss of dopamine from the forebrain striatal region, due to dopaminergic neuronal death in the midbrain substantia nigra pars compacta. PD with multifactorial etiology is believed to ideally require a drug or different drugs that act(s) at multiple sites of action for symptomatic relief. Replenishing striatal dopamine by providing L-3,4-dihydroxyphenylalanine (l-DOPA) along with a peripheral aromatic amino acid decarboxylase inhibitor is the mainstay treatment for PD. Such prolonged therapy leads to debilitating effects, often worsening the affection. Interestingly some under-appreciated pharmaceutical compounds, including constituents of plants and nutraceuticals can synergize with l-DOPA to support mitochondrial function, suppress inflammation, ease oxidative stress, and in turn slow the progression of the disease. Tea and other dietary polyphenols are shown to provide relief to the disease syndromes and provide neuroprotection in cellular and animal models of PD. At par with these findings, random epidemiological studies in certain populations of the world support habitual tea drinking to reduce the risk of PD. The present review addresses how these tea constituents work at the cellular level to render effective control of the disease syndromes and suggests that tea synergizes with established drugs, such as l-DOPA to maximize their effects at certain levels in the disease phenotype-inducing canonical pathways of PD.
Assuntos
Antiparkinsonianos/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Polifenóis/metabolismo , Chá/metabolismo , Animais , Antiparkinsonianos/administração & dosagem , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Sinergismo Farmacológico , Humanos , Levodopa/administração & dosagem , Levodopa/metabolismo , Polifenóis/administração & dosagemRESUMO
BACKGROUND: Bilateral intracerebroventricular (ICV) administration of streptozotocin (STZ) causes Alzheimer's disease (AD)-type neurodegeneration in rats. The model is increasingly used for investigating pathology and therapeutic strategies for AD. OBJECTIVE: The present study investigated cognitive abilities in rats infused with STZ-ICV in relation to hippocampal and cortical mitochondrial functions during a period of 60 days. METHODS: Cognitive functions were assayed in rats employing various mazes. Mitochondrial state-3-respiration, complex-I activity and dynamin related protein-1 (DRP-1) expression were measured respectively by oxygraph, spectrophotometry and immunoblot assay. Amyloidosis was investigated employing Congo red staining. RESULTS: One-time ICV-STZ infused animals exhibited body-weight loss and impaired cognitive ability from 14(th) day post-infusion. A significant loss of mitochondrial electron transport chain complex-I activity in the hippocampi and cortices was found by 14 days, and persisted up to 60 days following ICV-STZ infusion. Mitochondrial state-3 respiration was unaltered in these brain regions by 14 days, but significantly decreased from 21 days after STZ administration. DRP-1 expression was significantly increased in the hippocampi and cortices of these animals 21 days after infusion, but persisted only in the hippocampi up to 60 days. Congophilic granules indicative of amyloidosis were detected in the hippocampus by 21 days. CONCLUSION: Our results suggest that the non-genetic sporadic AD (sAD) rat model developed by single-time STZ-ICV infusion exhibits protein aggregation and dementia probably resulting from increased mitochondrial fragmentation and functional aberrations. The present study reinforces the validity of this model for studying pathogenesis and potential therapies of sAD.
Assuntos
Antibióticos Antineoplásicos/toxicidade , Transtornos Cognitivos/induzido quimicamente , Doenças Mitocondriais/induzido quimicamente , Estreptozocina/toxicidade , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Colina O-Acetiltransferase/metabolismo , Citrato (si)-Sintase/metabolismo , Transtornos Cognitivos/complicações , Transtornos Cognitivos/patologia , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Injeções Intraventriculares , Aprendizagem em Labirinto/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Doenças Mitocondriais/complicações , Proteínas do Tecido Nervoso/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
Serotonergic system has long been implicated in the aetiology of autism spectrum disorders (ASD), since platelet hyperserotonemia is consistently observed in a subset of autistic patients, who respond well to selective serotonin reuptake inhibitors. Apart from being a neurotransmitter, serotonin functions as a neurotrophic factor directing brain development and as an immunoregulator modulating immune responses. Serotonin transporter (SERT) regulates serotonin level in lymphoid tissues to ensure its proper functioning in innate and adaptive responses. Immunological molecules such as cytokines in turn regulate the transcription and activity of SERT. Dysregulation of serotonergic system could trigger signalling cascades that affect normal neural-immune interactions culminating in neurodevelopmental and neural connectivity defects precipitating behavioural abnormalities, or the disease phenotypes. Therefore, we suggest that a better understanding of the cross talk between serotonergic genes, immune systems and serotonergic neurotransmission will open wider avenues to develop pharmacological leads for addressing the core ASD behavioural deficits.