Ebselen attenuates oxidative DNA damage and enhances its repair activity in the thalamus after focal cortical infarction in hypertensive rats.
Oxidative DNA damage has been proposed to be a major contributor to focal cerebral ischemic injury. However, little is known about the role of oxidative DNA damage in remote damage secondary to the primary infarction. In the present study, we investigated oxidative damage within the ventroposterior nucleus (VPN) after distal middle cerebral artery occlusion (MCAO) in hypertensive rats. We also examined the possible protective effect of ebselen, one glutathione peroxidase mimic, on delayed degeneration in the VPN after distal MCAO. Neuronal damage in the ipsilateral VPN was examined by Nissl staining. Oxidative DNA damage and base repair enzyme activity were assessed by analyzing immunoreactivity of 8-hydroxy-2'-deoxyguanosine (8-ohdG) and 8-oxoguanine DNA glycosylase (OGG1), respectively. The number of intact neurons in the ipsilateral VPN decreased by 52% compared to the contralateral side in ischemia group 2 weeks after distal cerebral cortical infarction. The immunoreactivity of 8-ohdG significantly increased while OGG1 immunoreactivity significantly decreased in the ipsilateral VPN 2 weeks after distal cortical infarction (all p<0.01). Compared with vehicle treatment, ebselen significantly attenuated the neuron loss, ameliorated ischemia-induced increase in 8-ohdG level as well as decrease in OGG1 level within the ipsilateral VPN (all p<0.01). OGG1 was further demonstrated to mainly express in neurons. These findings strongly suggest that oxidative DNA damage may be involved in the delayed neuronal death in the VPN region following distal MCAO. Furthermore, ebselen protects against the delayed damage in the VPN when given at 24 h following distal MCAO.
He
Meixia
M
Department of Neurology and Stroke Center, First Affiliated Hospital, Sun Yat-Sen University, No. 58 Zhongshan Road 2, Guangzhou 510080, PR China.
Xing
Shihui
S
Yang
Bo
B
Zhao
Liqun
L
Hua
Haiying
H
Liang
Zhijian
Z
Zhou
Wenliang
W
Zeng
Jinsheng
J
Pei
Zhong
Z
D000704:Analysis of Variance; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001393:Azoles / Q000494:pharmacology*; D002544:Cerebral Infarction / Q000150:complications / Q000201:enzymology* / Q000473:pathology; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects*; D005979:Glutathione Peroxidase / Q000378:metabolism; D006977:Hypertension, Renal / Q000150:complications* / Q000201:enzymology / Q000473:pathology; D007150:Immunohistochemistry; D054833:Isoindoles; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016566:Organoselenium Compounds / Q000494:pharmacology*; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D013788:Thalamus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D001393:Azoles; D054833:Isoindoles; D018696:Neuroprotective Agents; D016566:Organoselenium Compounds; C042986:ebselen; D005979:Glutathione Peroxidase