脑源性神经营养因子介导帕金森病的运动防治:作用与机制

Exercise prevention and treatment of Parkinson’s disease mediated by brain-derived neurotrophic factor:role and mechanism

背景:运动干预作为经济有效的非物理疗法,可有效上调脑源性神经营养因子表达进而防治帕金森病发生发展,但目前关于靶向脑源性神经营养因子的运动治疗策略在延缓帕金森病发生发展的潜在作用机制尚不明晰。目的:以脑源性神经营养因子和帕金森病的关系为切入点,分析帕金森病病理状态下运动对脑源性神经营养因子表达的特异性调控作用及机制,梳理脑源性神经营养因子介导下不同运动方式对帕金森病的改善效果,并阐明靶向脑源性神经营养因子的运动治疗策略在防治帕金森病的潜在作用机制,旨在为运动防治帕金森病提供新的理论依据。方法:以“帕金森病,脑源性神经营养因子,神经保护,多巴胺,神经元异常凋亡,神经炎症反应,突触可塑性,运动”等为中文检索词;以“Parkinson’s disease,BDNF,Neuroprotection,neuroinflammation,synaptic plasticity”等为英文检索词,分别检索中国知网、万方数据库、PubMed和Web of Science数据库,搜寻各数据库建库至2024年2月发表的所有研究文献,根据纳排标准共获得核心相关文献98篇。结果与结论:①在帕金森病理背景下,运动可通过促进肌因子鸢尾素大量分泌,并降低色氨酸-犬尿氨酸代谢途径紊乱特异性调控脑源性神经营养因子表达。②有氧运动,尤其是特殊有氧运动(动物:旋转杆步行/人类:北欧健走)以及多模式运动可显著上调脑源性神经营养因子表达,进而改善帕金森病的运动症状,此外脑源性神经营养因子还介导身心运动(太极拳)对帕金森病患者认知障碍和睡眠障碍等非运动症状的有效调节。③运动诱导的高表达脑源性神经营养因子可能通过上调抗炎因子白细胞介素10、神经生长因子β和转化生长因子β表达,下调促炎因子肿瘤坏死因子α及白细胞介素1β表达,并抑制核转录因子κB信号通路表达降低小胶质细胞活性减轻神经炎症反应;增加酪氨酸羟化酶活性以促进多巴胺合成释放,并通过下调基质金属蛋白酶3及糖原合成酶激酶3β表达抑制α-突触核蛋白在丝氨酸129位点的磷酸化修饰,以防止神经异常凋亡;诱导突触效能的长时程增强发生,促进突触后致密区蛋白95及突触素大量表达以改善突触可塑性,发挥神经保护作。④鉴于脑源性神经营养因子在帕金森病发病进程及治疗中发挥重要作用,靶向脑源性神经营养因子的运动治疗策略将有助于推动帕金森病疾病“运动+药物”精准医疗的发展。但由于目前研究采用的运动处方较为单一,且研究焦点主要围绕运动症状而缺乏对非运动症状的考察,因此亟待学者采用更加统一和系统的运动处方,围绕非有氧运动类型对同一批帕金森病患者进行长期纵向跟踪研究,以此完善帕金森病运动防治领域研究的不足。

BACKGROUND:Exercise interventions,recognized for their economic and non-pharmaceutical efficacy,have demonstrated the potential to upregulate brain-derived neurotrophic factor levels,thereby offering a therapeutic approach to the prevention and management of Parkinson’s disease.However,the specific mechanisms by which exercise targeting brain-derived neurotrophic factor expression to delay Parkinson’s disease onset and progression are not clear.OBJECTIVE:To explore the interplay between brain-derived neurotrophic factor and Parkinson’s disease,to analyze the specific regulatory effect and mechanism of exercise on the expression of brain-derived neurotrophic factor in the pathological state of Parkinson’s disease,to review the improvement effect of different exercise methods mediated by brain-derived neurotrophic factor on Parkinson’s disease,to clarify the potential mechanism of exercise therapy targeting brain-derived neurotrophic factor in the prevention and treatment of Parkinson’s disease,in order to provide a new theoretical basis for exercise prevention and treatment of Parkinson’s disease.METHODS:A systematic literature review was conducted using“Parkinson’s disease,brain-derived neurotrophic factor,neuroprotection,dopamine,neuronal apoptosis,neuroinflammation,and synaptic plasticity”as Chinese keywords,and“Parkinson’s disease,BDNF,neuroprotection,neuroinflammation,and synaptic plasticity”as English keywords.Databases including CNKI,WanFang Data,PubMed,and Web of Science were searched for relevant articles published up to February 2024.Totally 98 core articles were selected based on inclusion and exclusion criteria.RESULTS AND CONCLUSION:(1)Within the pathophysiological framework of Parkinson’s disease,exercise has been shown to stimulate the release of the myokine Irisin and to specifically enhance brain-derived neurotrophic factor expression,counteracting kynurenine pathway metabolic dysregulation.(2)Aerobic activities,notably specialized forms such as Running on a Wheel with Electrical Stimulation(rotarod walking exercise)in animals and Nordic Walking in humans,along with multimodal exercise regimens,have been demonstrated to significantly enhance brain-derived neurotrophic factor expression.This upregulation is instrumental in ameliorating the motor symptoms associated with Parkinson’s disease.Furthermore,brain-derived neurotrophic factor is implicated in the beneficial modulation of non-motor symptoms,including cognitive and sleep disturbances,through the practice of mind-body interventions like Tai Chi.(3)Exercise-induced high expression of brain-derived neurotrophic factor exerts a neuroprotective effect through several mechanisms:By upregulating the expression of anti-inflammatory cytokines such as interleukin-10,nerve growth factor-beta,and transforming growth factor-beta,and concurrently downregulating the expression of pro-inflammatory cytokines such as tumor necrosis factor-alpha and interleukin-1 beta,thereby suppressing the activation of microglia via the inhibition of the nuclear factor-kappa B signaling pathway,leading to a reduction in neuroinflammatory responses;by augmenting the activity of tyrosine hydroxylase,which facilitates the synthesis and release of dopamine.This is complemented by the inhibition of matrix metalloproteinase-3 and glycogen synthase kinase-3 beta,preventing the hyperphosphorylation of alpha-synuclein at serine 129,thus counteracting abnormal neuronal apoptosis.By inducing long-term potentiation and promoting the robust expression of post-synaptic density protein 95 and synaptophysin,thereby enhancing synaptic plasticity and exerting a neuroprotective influence that may delay the onset and progression of Parkinson’s disease.(4)Considering the pivotal role of brain-derived neurotrophic factor in Parkinson’s disease progression and treatment,targeted exercise therapies could advance“Exercise+Medicine”precision medicine for Parkinson’s disease.However,current research is limited by a narrow focus on motor symptoms and a lack of diverse exercise protocols.There is a need for more comprehensive,longitudinal studies using varied exercise modalities to better understand and address non-motor symptoms in Parkinson’s disease patients to improve the lack of research in the field of Parkinson’s disease exercise prevention and treatment.