DDPH: improving cognitive deficits beyond its alpha 1-adrenoceptor antagonism in chronic cerebral hypoperfused rats.
DDPH (1-(2, 6-dimethylphenoxy)-2-(3, 4-dimethoxyphenylethylamino) propane hydrochloride), a candidate drug known to be an alpha(1)-adrenoceptor antagonist, can efficiently penetrate through blood brain barrier and inhibit the contraction of vascular smooth muscle in the brain. In rats with chronic cerebral hypoperfusion after permanent bilateral carotid artery ligation, we found that DDPH treatment at 6 or 12 mg/kg per day for 30 days significantly reversed pathological changes such as glial cell proliferation and nuclei shrinkage and reduced neuronal cell loss. In vivo electrophysiological studies revealed that DDPH increased long-term potentiation that was inhibited in these animals. In water maze tests, the percentage of time spent in the target quadrant (Q3) for ischemic rats (20.17+/-2.87%) was much shorter than that for the sham rats (45.39+/-3.68%), but DDPH at 12 mg/kg increased the time (39.58+/-3.77%) spent in Q3 in ischemic rats by 96.23%. These data suggested that DDPH improved the learning and memory performance significantly in rats with ischemia induced by bilateral carotid artery ligation. DDPH also lowered the levels of malondialdehyde (MDA), which was increased in the hypoperfused rats, and enhanced the activities of superoxide dismutase (SOD) and glutathione peroxidase, which were decreased in these rats. Further more, immunohistochemistry, RT-PCR assays and Western blot study demonstrated that DDPH attenuated the decreased expression of NMDAR2B (NR2B) in cortex and hippocampal CA1 region of the rats after bilateral carotid artery ligation. Our results suggest that DDPH may have favorable effects for the subjects in cerebrovascular insufficiency state following ischemic stroke.
He
Zhi
Z
Department of Pharmacology, School of Basic Medical Sciences, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, PR China.
Huang
Lin
L
Wu
Yan
Y
Wang
Jianzhi
J
Wang
Hongxing
H
Guo
Lianjun
L
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism; D002560:Cerebrovascular Circulation; D002908:Chronic Disease; D003072:Cognition Disorders / Q000188:drug therapy*; D005979:Glutathione Peroxidase / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D017774:Long-Term Potentiation; D008297:Male; D008315:Malondialdehyde / Q000032:analysis; D018782:Maze Learning; D010627:Phenethylamines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000032:analysis / Q000235:genetics; D013482:Superoxide Dismutase / Q000378:metabolism
D058668:Adrenergic alpha-1 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; C121001:NR2B NMDA receptor; D010627:Phenethylamines; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; C057485:1-(2,6-dimethylphenoxy)-2-(3,4-dimethoxyphenylethylamino)propane; D008315:Malondialdehyde; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase