title: Lamotrigine attenuates deficits in synaptic plasticity and accumulation of amyloid plaques in APP/PS1 transgenic mice.
abstract: Hyperactivity and its compensatory mechanisms may causally contribute to synaptic and cognitive deficits in Alzheimer's disease (AD). Blocking the overexcitation of the neural network, with levetiracetam (LEV), a sodium channel blocker applied in the treatment of epilepsy, prevented synaptic and cognitive deficits in human amyloid precursor protein (APP) transgenic mice. This study has brought the potential use of antiepileptic drugs (AEDs) in AD therapy. We showed that the chronic treatment with lamotrigine (LTG), a broad-spectrum AED, suppressed abnormal spike activity, prevented the loss of spines, synaptophysin immunoreactivity, and neurons, and thus attenuated the deficits in synaptic plasticity and learning and memory in APP and presenilin 1 (PS1) mice, which express human mutant APP and PS1. In contrast with LEV, which failed to reduce the generation of amyloid β, the chronic LTG treatment reduced the cleavage of APP by β-secretase and thus the numbers and the size of amyloid plaques in the brains of APP and PS1 mice. Moreover, the levels of brain-derived neurotrophic growth factor (BDNF) and nerve growth factor (NGF) were enhanced in the brains of APP and PS1 mice by the chronic LTG treatment. Therefore, these observations demonstrate that LTG attenuates AD pathology through multiple mechanisms, including modulation of abnormal network activity, reduction of the generation of amyloid beta and upregulation of BDNF and NGF.
authors.affiliation: Affiliated Bayi Brain Hospital, Beijing Military Hospital, PLA and PhD Student Program of Southern Medical University, Beijing, China.
authors.forename: Mao-Ying
authors.initials: MY
authors.lastname: Zhang
authors.affiliation: Affiliated Bayi Brain Hospital, Beijing Military Hospital, PLA and PhD Student Program of Southern Medical University, Beijing, China.
authors.forename: Chuan-Yi
authors.initials: CY
authors.lastname: Zheng
authors.affiliation: Affiliated Bayi Brain Hospital, Beijing Military Hospital, PLA and PhD Student Program of Southern Medical University, Beijing, China.
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Zou
authors.affiliation: Affiliated Bayi Brain Hospital, Beijing Military Hospital, PLA and PhD Student Program of Southern Medical University, Beijing, China.
authors.forename: Jian-Wei
authors.initials: JW
authors.lastname: Zhu
authors.affiliation: Affiliated Bayi Brain Hospital, Beijing Military Hospital, PLA and PhD Student Program of Southern Medical University, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Affiliated Bayi Brain Hospital, Beijing Military Hospital, PLA and PhD Student Program of Southern Medical University, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, Suzhou, Jiangsu Province, China.
authors.forename: Chun-Feng
authors.initials: CF
authors.lastname: Liu
authors.affiliation: Department of Physiology, Dalian Medical University, Dalian, China.
authors.forename: Qi-Fa
authors.initials: QF
authors.lastname: Li
authors.affiliation: Department of Anatomy and Developmental Biology, Monash University, Clayton, Australia.
authors.forename: Zhi-Cheng
authors.initials: ZC
authors.lastname: Xiao
authors.affiliation: Department of Physiology, Dalian Medical University, Dalian, China. Electronic address: lishao89@hotmail.com.
authors.forename: Shao
authors.initials: S
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Institute of Neuroscience, Soochow University, Suzhou, Jiangsu Province, China. Electronic address: h999.judy@gmail.com.
authors.forename: Quan-Hong
authors.initials: QH
authors.lastname: Ma
authors.affiliation: Affiliated Bayi Brain Hospital, Beijing Military Hospital, PLA and PhD Student Program of Southern Medical University, Beijing, China. Electronic address: zjxuruxiang@163.com.
authors.forename: Ru-Xiang
authors.initials: RX
authors.lastname: Xu
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology* / Q000627:therapeutic use*; D001921:Brain / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D000077213:Lamotrigine; D007858:Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020932:Nerve Growth Factor / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects*; D058225:Plaque, Amyloid / Q000378:metabolism*; D014227:Triazines / Q000494:pharmacology* / Q000627:therapeutic use*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016229:Amyloid beta-Peptides; D000927:Anticonvulsants; D019208:Brain-Derived Neurotrophic Factor; D014227:Triazines; D020932:Nerve Growth Factor; D000077213:Lamotrigine
keywords: Alzheimer's disease; Antiepileptic drug; Hyperexcitability; Lamotrigine; Synaptic plasticity