Beneficial effects of TDN-345, a novel Ca2+ antagonist, on ischemic brain injury and cerebral glucose metabolism in experimental animal models with cerebrovascular lesions.
The effects of TDN-345 on mortality and ischemic neurological deficit following transient global cerebral ischemia in Mongolian gerbils and also the rate of local cerebral glucose utilization (LCGU) in stroke-prone spontaneously hypertensive rats (SHRSP) with cerebrovascular lesions were investigated. In Mongolian gerbils, ischemia was produced by clamping the bilateral common carotid arteries for 15 min. TDN-345 (0.1-1.0 mg/kg) dose-dependently decreased the mortality and ischemic neurological deficit score when administered orally twice, 60 min before ischemia and 90 min after recirculation. Additionally, TDN-345 (0.2 or 1.0 mg/kg, p.o. once daily for 3 weeks after the onset of stroke) decreased the mortality and recurrence of stroke in SHRSP. To determine the site of action of TDN-345 in the brain, the rate of LCGU in various brain regions in SHRSP with stroke was examined using a [14C]2-deoxy-D-glucose method. The rate of LCGU decreased significantly in all the brain regions in SHRSP with stroke compared with Wistar-Kyoto (WKY) control rats, whereas the reduction in the rate of LCGU in SHRSP with stroke was prevented by TDN-345 treatment, especially in the sensorimotor cortex and locus coeruleus. These results suggest that TDN-345 has therapeutic efficacy in the treatment of cerebrovascular disease.
Nakayama
T
T
Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Yodogawa-ku, Osaka, Japan. Nakayama_Takahiro@takeda.co.jp
Nagisa
Y
Y
Imamoto
T
T
Nagai
Y
Y
D000818:Animals; D001921:Brain / Q000098:blood supply* / Q000378:metabolism; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002561:Cerebrovascular Disorders / Q000188:drug therapy / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005849:Gerbillinae; D005947:Glucose / Q000378:metabolism*; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D018696:Neuroprotective Agents; D013141:Spiro Compounds; C108126:TDN 345; D005947:Glucose