Neuroprotective And Neurorestorative Signaling Mechanisms

神经保护和神经恢复信号机制

• 批准号: 8552362
• 负责人: Mark Mattson
• 金额: $ 53.65万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8552362
• 关键词: Adrenalectomy; Adverse effects; Alzheimer' s Disease; Animal Model; Antioxidants; Attenuated; Autonomic Dysfunction; Autonomic nervous system; Autopsy; Behavior; Botanicals; Brain; Brain Stem; Brain-Derived Neurotrophic Factor; Caenorhabditis elegans; Cardiovascular system; Cell Nucleus; Cells; Cellular Stress Response; Cessation of life; Cognitive; Complement; Complement 1q; Congenital neurologic anomalies; Control Groups; Corticosterone; Diabetes Mellitus; Diet; Disease; Disease Progression; Dose; Electroconvulsive Therapy; Energy Metabolism; Enzymes; Exercise; Exhibits; Experimental Models; Exposure to; Fasting; Free Radicals; Functional disorder; Gene Expression; Goals; Growth Factor; Heart; Heart Rate; Hippocampus (Brain); Hormones; Human; Huntington Disease; Individual; Intravenous Immunoglobulins; Ion Channel; Ischemic Stroke; Kainic Acid; Lead; Learning; Link; Longevity; Mammalian Cell; Measures; Mediating; Mediator of activation protein; Memory impairment; Metabolic stress; Modeling; Molecular; Molecular Chaperones; Molecular Weight; Motor; Mus; Mutant Strains Mice; Naphthoquinones; Nematoda; Nerve Degeneration; Neurologic; Neuronal Dysfunction; Neurons; Neuropeptides; Neurotoxins; Operative Surgical Procedures; Overweight; Oxidative Stress; Parkinson Disease; Pathology; Pathway interactions; Patients; Peptides; Performance; Pesticides; Physiological; Phytochemical; Potential Energy; Process; Proteins; Rattus; Regimen; Regulation; Reporter; Reporting; Resistance; Rest; Screening procedure; Series; Signal Pathway; Signal Transduction; Staging; Stress; Stroke; Substantia nigra structure; Supplementation; Symptoms; Up-Regulation; Vitamin K 3; age effect; analog; anti aging; biological adaptation to stress; brain cell; cytokine; dietary restriction; dopaminergic neuron; exenatide; feeding; genetic analysis; glucagon-like peptide; human Huntingtin protein; human subject; in vivo; inhibitor/antagonist; mouse model; mutant; nervous system disorder; neuron loss; neuroprotection; neurorestoration; neurotrophic factor; new therapeutic target; novel; plumbagin; prevent; research clinical testing; research study; response; restraint stress; synuclein; thermal stress; transcription factor

We have identified several growth factors and cytokines that can protect neurons against dysfunction and death in experimental models of Alzheimers disease, Parkinsons disease and stroke. These trophic factors activate signaling pathways that stimulate the expression of genes whose encoded proteins increase resistance of neurons to oxidative and metabolic stress. Neuroprotective Actions of BDNF. We have found that brain-derived neurotrophic factor (BDNF) is a key mediator of the neuroprotective effects of dietary restriction in animal models of Parkinsons and Huntingtons diseases. We identified GLP-1 (glucagon-like peptide 1) as a neuroprotective neuropeptide with the potential to ameliorate neuronal dysfunction and degeneration in some neurodegenerative conditions. We have demonstrated the ability of exendin-4, a GLP-1 analog used to treat diabetes, to ameliorate neurological deficits in animal models of stroke, Huntington's disease, Parkinson's disease and Alzheimer's disease. We are currently performing a clincial trial of exendin-4 in patients who are in the early stages of Alzheimer's disease. We have identified several novel neuroprotective strategies in animal models including: intermittent electroconvulsive shock therapy slows disease progression and extends survival in Huntingtin mutant mice; Alternate day fasting protects the brain against ischemic stroke by a mechanism involving the upregulation of BDNF, protein chaperones and antioxidant enzymes in brain cells; treatment of mice with intravenous immunoglobulin or a specific peptide inhibitor of the complement protein C1q, is highly neuroprotective in stroke model. Experimental models of diabetes in rats and mice have demonstrated that reduction of corticosterone (CORT; a stress hormone) reduces learning and memory deficits and attenuates loss of neuronal viability and plasticity. In contrast to the negative associations of elevated GC levels, CORT is moderately elevated in dietary restriction (DR) paradigms which are associated with many healthy anti-aging effects including neuroprotection. We demonstrate here in rats that ablating CORT by adrenalectomy (ADX) with replenishment to relatively low levels (30% below that of controls) prior to the onset of a DR regimen (ADX-DR) followed by central administration of the neurotoxin, kainic acid (KA), significantly attenuates learning deficits in a 14-unit T-maze task. The performance of the ADX-DR KA group did not differ from a control group (CON) that did not receive KA and was fed ad libitum (AL). By contrast, the sham-operated DR (SHAM-DR KA) group, SHAM-AL KA group, and ADX-AL KA group demonstrated poorer learning behavior in this task compared to the CON group. Stereological analysis revealed equivalent DR-induced neuroprotection in the SH-DR KA and ADX-DR KA groups, as measured by cell loss in the CA2/CA3 region of the hippocampus, while substantial cell loss was observed in SH-AL and ADX-AL rats. A separate set of experiments was conducted with similar dietary and surgical treatment conditions but without KA administration to examine markers of neurotrophic activity, BDNF, transcriptions factors (pCREB), and chaperone proteins (HSP-70). Under these conditions, we noted elevations in both BDNF and pCREB in ADX DR rats compared to the other groups; whereas, HSP-70, was equivalently elevated in ADX-DR and SH-DR groups and was higher than observed in both SH-AL and ADX-AL groups. These results support findings that DR protects hippocampal neurons against KA-induced cellular insult. However, this neuroprotective effect was further enhanced in rats with a lower-than control level of CORT resulting from ADX and maintained by exogenous CORT supplementation. Our results then suggest that DR-induced physiological elevation of GC may have negative functional consequences to DR-induced beneficial effects. These negative effects, however, can be compensated by other DR-produced cellular and molecular protective mechanisms. Huntington's disease (HD) is associated with profound autonomic dysfunction including dysregulation of cardiovascular control often preceding cognitive or motor symptoms. Brain-derived neurotrophic factor (BDNF) levels are decreased in the brains of HD patients and HD mouse models, and restoring BDNF levels prevents neuronal loss and extends survival in HD mice. We reasoned that heart rate changes in HD may be associated with altered BDNF signaling in cardiovascular control nuclei in the brainstem. Here we show that heart rate is elevated in HD (N171-82Q) mice at presymptomatic and early disease stages, and heart rate responses to restraint stress are attenuated. BDNF levels were significantly reduced in brainstem regions containing cardiovascular nuclei in HD mice and human HD patients. Central administration of BDNF restored the heart rate to control levels. Our findings establish a link between diminished BDNF expression in brainstem cardiovascular nuclei and abnormal heart rates in HD mice, and suggest a novel therapeutic target for correcting cardiovascular dysfunction in HD. Hormesis occurs when a low level stress elicits adaptive beneficial responses that protect against subsequent exposure to severe stress. Recent findings suggest that mild oxidative and thermal stress can extend lifespan by hormetic mechanisms. Here we show that the botanical pesticide plumbagin, while toxic to C. elegans nematodes at high doses, extends lifespan at low doses. Because plumbagin is a naphthoquinone that can generate free radicals in vivo, we investigated whether it extends lifespan by activating an adaptive cellular stress response pathway. The C. elegans cap'n'collar (CNC) transcription factor, SKN-1, mediates protective responses to oxidative stress. Genetic analysis showed that skn-1 activity is required for lifespan extension by low-dose plumbagin in C. elegans. Further screening of a series of plumbagin analogs identified three additional naphthoquinones that could induce SKN-1 targets in C. elegans. Naphthazarin showed skn-1dependent lifespan extension, over an extended dose range compared to plumbagin, while the other naphthoquinones, oxoline and menadione, had differing effects on C. elegans survival and failed to activate ARE reporter expression in cultured mammalian cells. Our findings reveal the potential for low doses of naturally occurring naphthoquinones to extend lifespan by engaging a specific adaptive cellular stress response pathway. Parkinson's disease (PD) patients often exhibit impaired regulation of heart rate by the autonomic nervous system (ANS) that may precede motor symptoms in many cases. Results of autopsy studies suggest that brainstem pathology, including the accumulation of -synuclein, precedes damage to dopaminergic neurons in the substantia nigra in PD. However, the molecular and cellular mechanisms responsible for the early dysfunction of brainstem autonomic neurons are unknown. Here we report that mice expressing a mutant form of -synuclein that causes familial PD exhibit aberrant autonomic control of the heart characterized by elevated resting heart rate and an impaired cardiovascular stress response, associated with reduced parasympathetic activity and accumulation of -synuclein in the brainstem. These ANS abnormalities occur early in the disease process. Adverse effects of -synuclein on the control of heart rate are exacerbated by a high energy diet and ameliorated by intermittent energy restriction. Our findings establish a mouse model of early dysregulation of brainstem control of the cardiovascular system in PD, and further suggest the potential for energy restriction to attenuate ANS dysfunction, particularly in overweight individuals.

我们已经在阿尔茨海默病、帕金森病和中风的实验模型中发现了几种可以保护神经元免受功能障碍和死亡的生长因子和细胞因子。这些营养因子激活信号通路，刺激基因的表达，这些基因编码的蛋白质增加神经元对氧化和代谢应激的抵抗力。BDNF的神经保护作用。我们发现脑源性神经营养因子（BDNF）是饮食限制对帕金森病和亨廷顿病动物模型的神经保护作用的关键介质。