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
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
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
Silymarin, a C25 containing flavonoid from the plant Silybum marianum, has been the gold standard drug to treat liver disorders associated with alcohol consumption, acute and chronic viral hepatitis, and toxin-induced hepatic failures since its discovery in 1960. Apart from the hepatoprotective nature, which is mainly due to its antioxidant and tissue regenerative properties, Silymarin has recently been reported to be a putative neuroprotective agent against many neurologic diseases including Alzheimer's and Parkinson's diseases, and cerebral ischemia. Although the underlying neuroprotective mechanism of Silymarin is believed to be due to its capacity to inhibit oxidative stress in the brain, it also confers additional advantages by influencing pathways such as ß-amyloid aggregation, inflammatory mechanisms, cellular apoptotic machinery, and estrogenic receptor mediation. In this review, we have elucidated the possible neuroprotective effects of Silymarin and the underlying molecular events, and suggested future courses of action for its acceptance as a CNS drug for the treatment of neurodegenerative diseases.
Assuntos
Doenças Neurodegenerativas/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , Silimarina/uso terapêutico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Doenças do Sistema Nervoso Central/metabolismo , Doenças do Sistema Nervoso Central/patologia , Doenças do Sistema Nervoso Central/prevenção & controle , Humanos , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Doença de Parkinson/prevenção & controle , Receptores de Estrogênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Silimarina/metabolismo , Silimarina/farmacologiaRESUMO
The dopamine precursor, L-3,4-dihydroxyphenylalanine (L-DOPA), is the preferred drug for Parkinson's disease, but long-term treatment results in the drug-induced dyskinesias and other side effects. This study was undertaken to examine whether melatonin could potentiate low dose L-DOPA effects in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced experimental parkinsonism. Mice were treated with the parkinsonian neurotoxin, MPTP, and different doses of melatonin and low doses of L-DOPA. Behavior, striatal histology, and dopamine metabolism were evaluated on the 7th day. MPTP-induced striatal dopamine loss was not modified by melatonin administration (10-30 mg/kg; i.p. at 10-hr intervals, 6 times; or at 2-hr intervals, by day). However, low doses of L-DOPA (5 mg/kg, by oral gavage) administered alone or along with melatonin (10 mg/kg, i.p.) twice everyday for 2 days, 10 hr apart, after two doses of MPTP significantly attenuated striatal dopamine loss and provided improvements in both catalepsy and akinesia. Additionally, Golgi-impregnated striatal sections showed preservation of the medium spiny neurons, which have been damaged in MPTP-treated mouse. The results demonstrated that melatonin, but not L-DOPA, restored spine density and spine morphology of medium spiny neurons in the striatum and suggest that melatonin could be an ideal adjuvant to L-DOPA therapy in Parkinson's disease, and by the use of this neurohormone, it is possible to bring down the therapeutic doses of L-DOPA.
Assuntos
Antiparkinsonianos/farmacologia , Depressores do Sistema Nervoso Central/farmacologia , Corpo Estriado/metabolismo , Dendritos/metabolismo , Levodopa/farmacologia , Melatonina/farmacologia , Doença de Parkinson Secundária/tratamento farmacológico , Animais , Antiparkinsonianos/agonistas , Depressores do Sistema Nervoso Central/agonistas , Corpo Estriado/patologia , Dendritos/patologia , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Levodopa/agonistas , Intoxicação por MPTP/tratamento farmacológico , Intoxicação por MPTP/metabolismo , Intoxicação por MPTP/patologia , Melatonina/agonistas , Camundongos , Camundongos Endogâmicos BALB C , Doença de Parkinson Secundária/metabolismo , Doença de Parkinson Secundária/patologiaRESUMO
We evaluated the hydroxyl radical (*OH) scavenging action of nonsteroidal anti-inflammatory drugs (NSAIDs), sodium salicylate (SA), diclofenac and celecoxib in Fenton's reaction and their neuroprotective effects in 1-methyl-4-phenylpyridinium (MPP(+))-induced striatal dopamine (DA) depletion in rats. Salicylate hydroxylation procedure employing HPLC-electrochemistry was used to assay formation of *OH in Fenton's reaction in test tubes. While SA dose- and time-dependently hydroxylated itself and inactivated *OH, celecoxib (up to 10 mM) showed no effect on *OH formation and diclofenac caused a reduction in *OH generation only at high doses (100 microM-10 mM). Administration of the non-selective cyclooxygenase (COX) inhibitor, SA (50, 100 mg/kg, i.p.) significantly attenuated striatal DA depletion caused by intrastriatal infusion of MPP(+) (100 nmol in 4 microl). Treatment with another nonselective, reversible COX inhibitor, diclofenac (5, 10 mg/kg) did not protect against MPP(+)-induced DA depletion. The selective COX-2 inhibitor, celecoxib (2.5-50 mg/kg) treatment exacerbated MPP(+)-induced decrease in DA. Failure of celecoxib or diclofenac to render protection in animals against MPP(+)-induced DA depletion indicates absence of prostaglandin involvement in MPP(+) action. These results also suggest that the neuroprotective ability of SA is independent of prostaglandin mediation. A relationship between inactivation of *OH by SA and its ability to protect DA depletion in the striatum caused by MPP(+) indicates a direct involvement of *OH in the action of this neurotoxin. The present study establishes potent neuroprotective activity of SA and suggests the use of aspirin in adjuvant therapy in Parkinson's disease.