Modafinil‐coated nanoparticle increases expressions of brain‐derived neurotrophic factor, glial cell line‐derived neurotrophic factor and neuronal nuclear protein, and protects against middle cerebral artery occlusion‐induced neuron apoptosis in the rat hippocampus

Brain-derived neurotrophic factor (BDNF), acting through the high-affinity receptor tyrosine kinase (TrkB), is widely distributed throughout the central nervous system and displays in vitro trophic effects on a wide range of neuronal cells, including hippocampal, cerebellar, and cortical neurons. In vivo, BDNF rescues motorneurons, hippocampal, and substantia nigral dopaminergic cells from traumatic and toxic brain injury. After transient middle cerebral artery occlusion (MCAO), upregulation of BDNF-mRNA in cortical neurons suggests that BDNF potentially plays a neuroprotective role in focal cerebral ischemia. In the current study, BDNF (2.1 μg/d) in vehicle or vehicle alone (controls) was delivered intraventricularly for 8 days, beginning 24 hours before permanent middle cerebral artery occlusion by intraluminal suture in Wistar rats (n = 13 per group). There were no differences in physiological variables recorded during surgery for the two groups. Neurological deficit (0 to 4 scale), which was assessed on a daily basis, improved in BDNF-treated animals compared with controls ( P < 0.05; analysis of variance and Scheffe's test). There were no significant differences in weight in BDNF-treated animals and controls during the experiment. After elective killing on day 7 after MCAO, brains underwent 2,3,5-triphenyltetrazolium chloride staining for calculation of the infarct volume and for histology (hematoxylin and eosin and glial fibrillary acid protein). The mean total infarct volume was 83.1 ± 27.1 mm3 in BDNF-treated animals and 139.2 ± 56.4 mm3 in controls (mean ± SD; P < 0.01, unpaired, two-tailed t-test). The cortical infarct volume was 10.8 ± 7.1 mm3 in BDNF-treated animals and 37.9 ± 19.8 mm3 in controls (mean ± SD; P < 0.05; unpaired, two-tailed t-test), whereas ischemic lesion volume in caudoputaminal infarction was not significantly different. These results show that pretreatment with intraventricular BDNF reduces infarct size after focal cerebral ischemia in rats and support the hypothesis of a neuroprotective role for BDNF in stoke.

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Regulation of Brain-Derived Neurotrophic Factor Gene Expression after Transient Middle Cerebral Artery Occlusion with and without Brain Damage

Experimental Neurology ◽

10.1006/exnr.1995.1085 ◽

1995 ◽

Vol 136 (1) ◽

pp. 73-88 ◽

Cited By ~ 195

Author(s):

Zaal Kokaia ◽

Qi Zhao ◽

Merab Kokaia ◽

Eskil Elmér ◽

Madis Metsis ◽

...

Keyword(s):

Gene Expression ◽

Middle Cerebral Artery ◽

Middle Cerebral Artery Occlusion ◽

Brain Damage ◽

Cerebral Artery ◽

Neurotrophic Factor ◽

Brain Derived Neurotrophic Factor ◽

Artery Occlusion ◽

Factor Gene ◽

Cerebral Artery Occlusion

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Histone Methyltransferase Dot1L Contributes to RIPK1 Kinase‐Dependent Apoptosis in Cerebral Ischemia/Reperfusion

Journal of the American Heart Association ◽

10.1161/jaha.121.022791 ◽

2021 ◽

Author(s):

Jinghuan Wang ◽

Wen Zhong ◽

Haibi Su ◽

Jie Xu ◽

Di Yang ◽

...

Keyword(s):

Cerebral Ischemia ◽

Middle Cerebral Artery ◽

Middle Cerebral Artery Occlusion ◽

Cerebral Artery ◽

Promoter Region ◽

Glucose Deprivation ◽

Artery Occlusion ◽

Oxygen Glucose Deprivation ◽

Cerebral Artery Occlusion ◽

Neuron Apoptosis

Background Neuron apoptosis is a pivotal process for brain damage in cerebral ischemia. Dot1L (disruptor of telomeric silencing 1‐like) is only known histone H3K79 methyltransferase. It is not clear whether the role and mechanism of Dot1L on cerebral ischemia is related to regulate neuron apoptosis. Methods and Results We use a combination of mice middle cerebral artery occlusion stroke and neurons exposed to oxygen‐glucose deprivation followed by reoxygenation to investigate the role and mechanism of Dot1L on cerebral ischemia. We find knockdown or inhibition of Dot1L reversed ischemia‐induced neuronal apoptosis and attenuated the neurons injury treated by oxygen‐glucose deprivation followed by reoxygenation. Further, blockade of Dot1L prevents RIPK1 (receptor‐interacting protein kinase 1)‐dependent apoptosis through increased RIPK1 K63‐ubiquitylation and decreased formation of RIPK1/Caspase 8 complexes. In line with this, H3K79me3 enrichment in the promoter region of deubiquitin‐modifying enzyme A20 and deubiquitinase cylindromatosis gene promotes the increasing expression in oxygen‐glucose deprivation followed by reoxygenation ‐induced neuronal cells, on the contrary, oxygen‐glucose deprivation followed by reoxygenation decreases H3K79me3 level in the promoter region of ubiquitin‐modifying enzyme cIAP1 (cellular inhibitors of apoptosis proteins), and both these factors ultimately cause K63‐deubiquitination of RIPK1. Importantly, knockdown or inhibition of Dot1L in vivo attenuates apoptosis in middle cerebral artery occlusion mice and reduces the extent of middle cerebral artery occlusion ‐induced brain injury. Conclusions These data support for the first time, to our knowledge, that Dot1L regulating RIPK1 to the apoptotic death trigger contributes to cerebral ischemia injury. Therefore, targeting Dot1L serves as a new therapeutic strategy for ischemia stroke.

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