Relationship of the Met Allele of the Brain-Derived Neurotrophic Factor Val66met Polymorphism to Memory After Aneurysmal Subarachnoid Hemorrhage

Vilkki, Juhani; Lappalainen, Jaakko; Juvela, Seppo; Kanarek, Katarzyna; Hernesniemi, Juha; Siironen, Jari

doi:10.1227/01.neu.0000320382.21577.8e

Cited by 30 publications

(22 citation statements)

References 16 publications

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“…Variations in tumor necrosis factor-a, insulin-like growth factor 1, and brain-derived neurotrophic factor polymorphisms have been linked in some [27][28][29] but not all studies to outcome after SAH [30]. Nitric oxide produced by endothelial nitric oxide synthase prevents thrombosis and polymorphisms in this enzyme and in fibrinolytic enzymes that have been associated with DIND and outcome after SAH also could affect the response to SIRS [31][32][33][34].…”

Section: Discussionmentioning

confidence: 99%

Impact of Systemic Inflammatory Response Syndrome on Vasospasm, Cerebral Infarction, and Outcome After Subarachnoid Hemorrhage: Exploratory Analysis of CONSCIOUS-1 Database

et al. 2010

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Section: Discussionmentioning

confidence: 99%

Impact of Systemic Inflammatory Response Syndrome on Vasospasm, Cerebral Infarction, and Outcome After Subarachnoid Hemorrhage: Exploratory Analysis of CONSCIOUS-1 Database

et al. 2010

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“…Identified as the first genetic alteration in the neurotrophin system, the BDNF has been implicated in conferring susceptibility to various neuropsychiatric disorders and altered episodic memory in patients with psychiatric disease (Sklar et al, 2002; Egan et al, 2003; Sen et al, 2003). Although studies on the impact of the BDNF polymorphism in the outcome after ischemic stroke are limited, clinical studies suggest a correlation of this BDNF polymorphism with poor outcome in hemorrhagic stroke patients (Siironen et al, 2007; Vilkki et al, 2008). …”

Section: Introductionmentioning

confidence: 99%

Genetic Variant of BDNF (Val66Met) Polymorphism Attenuates Stroke-Induced Angiogenic Responses by Enhancing Anti-Angiogenic Mediator CD36 Expression

Qin¹,

Kim²,

Ratan³

et al. 2011

J. Neurosci.

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Brain-derived neurotrophic factor (BDNF) has been shown to be necessary and sufficient for post-stroke recovery in rodents. From these observations, we and others have hypothesized that a common single nucleotide polymorphism (SNP) in the pro-domain of bdnf that leads to a methionine (Met) substitution for valine (Val) at codon 66 (Val66Met) will affect stroke outcome. Here we investigate the effect of the BDNF genetic variant on ischemic outcome by using mice with a genetic knock-in of the human BDNF variant in both alleles (BDNFMet/Met). Compared with wild-type mice, BDNFMet/Met mice exhibited reduced CNS BDNF levels without a discernable effect on infarct size. Diminished BDNF levels in BDNFMet/Met mice were associated with greater deficits in post-stroke locomotor functions. Additionally, the BDNFMet/Met mice showed reduced angiogenesis and elevated expression of thrombospondin-1 (TSP-1) and its receptor CD36, anti-angiogenic factors. To assess the functional role of CD36 in antagonizing angiogenic response in Met homozygosity at the BDNF locus, we crossed BDNFMet/Met mice with CD36 knock-out mice. The double-mutant mice rescued the angiogenic deficit associated with the BDNFMet/Met mice without alterations in BDNF levels, indicating that the behavioral deficit in BDNFMet/Met mice after stroke is partly related to an unfavorable balance in pro-angiogenic BDNF and anti-angiogenic TSP-1/CD36. The results suggest that CD36 inhibition may be a viable strategy to enhance angiogenesis and possible recovery in human stroke victims who are Met homozygotes at codon 66 of the BDNF locus.

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“…Moreover, BDNF is involved in the pathophysiology of SAH. For example, clinical evidence has shown that a BDNF polymorphism is associated with poor patient recovery from SAH (40, 41). Animal experiments have demonstrated that exogenous BDNF infusion or upregulation of its expression improves neurobehavioral outcomes after SAH (42, 43).…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective Roles of l-Cysteine in Attenuating Early Brain Injury and Improving Synaptic Density via the CBS/H2S Pathway Following Subarachnoid Hemorrhage in Rats

Wang

et al. 2017

Front. Neurol.

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l-Cysteine is a semi-essential amino acid and substrate for cystathionine-β-synthase (CBS) in the central nervous system. We previously reported that NaHS, an H2S donor, significantly alleviated brain damage after subarachnoid hemorrhage (SAH) in rats. However, the potential therapeutic value of l-cysteine and the molecular mechanism supporting these beneficial effects have not been determined. This study was designed to investigate whether l-cysteine could attenuate early brain injury following SAH and improve synaptic function by releasing endogenous H2S. Male Wistar rats were subjected to SAH induced by cisterna magna blood injection, and l-cysteine was intracerebroventricularly administered 30 min after SAH induction. Treatment with l-cysteine stimulated CBS activity in the prefrontal cortex (PFC) and H2S production. Moreover, l-cysteine treatment significantly ameliorated brain edema, improved neurobehavioral function, and attenuated neuronal cell death in the PFC; these effects were associated with a decrease in the Bax/Bcl-2 ratio and the suppression of caspase-3 activation 48 h after SAH. Furthermore, l-cysteine treatment activated the CREB–brain-derived neurotrophic factor (BDNF) pathway and intensified synaptic density by regulating synapse proteins 48 h after SAH. Importantly, all the beneficial effects of l-cysteine in SAH were abrogated by amino-oxyacetic acid, a CBS inhibitor. Based on these findings, l-cysteine may play a neuroprotective role in SAH by inhibiting cell apoptosis, upregulating CREB–BDNF expression, and promoting synaptic structure via the CBS/H2S pathway.

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Relationship of the Met Allele of the Brain-Derived Neurotrophic Factor Val66met Polymorphism to Memory After Aneurysmal Subarachnoid Hemorrhage

Cited by 30 publications

References 16 publications

Impact of Systemic Inflammatory Response Syndrome on Vasospasm, Cerebral Infarction, and Outcome After Subarachnoid Hemorrhage: Exploratory Analysis of CONSCIOUS-1 Database

Impact of Systemic Inflammatory Response Syndrome on Vasospasm, Cerebral Infarction, and Outcome After Subarachnoid Hemorrhage: Exploratory Analysis of CONSCIOUS-1 Database

Genetic Variant of BDNF (Val66Met) Polymorphism Attenuates Stroke-Induced Angiogenic Responses by Enhancing Anti-Angiogenic Mediator CD36 Expression

Neuroprotective Roles of l-Cysteine in Attenuating Early Brain Injury and Improving Synaptic Density via the CBS/H2S Pathway Following Subarachnoid Hemorrhage in Rats

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