Effects of sustained release formulation of thyrotropin-releasing hormone on learning impairments caused by scopolamine and AF64A in rodents.
The effects of a sustained-release formulation of thyrotropin-releasing hormone (TRH-SR) on learning impairments induced by scopolamine and a cholinergic neurotoxin, ethylcholine aziridinium ion (AF64A), were examined in rodents. Subcutaneous injection of TRH-SR (2.8 mg/kg as free TRH) produced a sustained increase in immunoreactive plasma TRH levels up to about 2 weeks after dosing in rats. TRH-SR (0.56 and 2.8 mg/kg) given subcutaneously 7 days before the acquisition trial markedly ameliorated scopolamine-induced amnesia in mice, as evaluated with a passive avoidance task. Repeated administration of TRH for 7 days at doses of 0.2-5 mg/kg s.c. elicited a dose-dependent recovery from amnesia induced by scopolamine, whereas only the group treated with 5 mg/kg/day showed a significant improvement. The rats with bilateral intracerebroventricular injection of AF64A (3.75 nmol/brain) showed a significant impairment in the water maze task 2 weeks after surgery. TRH-SR (0.56 and 2.8 mg/kg) also exhibited a dose-dependent ameliorating action on the deficit. These findings indicate that TRH-SR ameliorates learning impairments produced by scopolamine and AF64A, and suggest that continuous infusion of TRH may have a potent learning and memory improving action at low doses.
Miyamoto
M
M
Pharmaceutical Research Laboratories I, Takeda Chemical Industries, Ltd., Osaka, Japan.
Hirai
K
K
Takahashi
H
H
Kato
K
K
Nishiyama
M
M
Okada
H
H
Nagaoka
A
A
D000647:Amnesia / Q000139:chemically induced / Q000188:drug therapy; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001388:Aziridines / Q000633:toxicity*; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002794:Choline / Q000031:analogs & derivatives* / Q000633:toxicity; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D007276:Injections, Intraventricular; D007279:Injections, Subcutaneous; D007858:Learning / Q000187:drug effects*; D008297:Male; D008568:Memory / Q000187:drug effects*; D051379:Mice; D009466:Neuromuscular Blocking Agents / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D012601:Scopolamine / Q000633:toxicity*; D013973:Thyrotropin-Releasing Hormone / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use
D001388:Aziridines; D003692:Delayed-Action Preparations; D009466:Neuromuscular Blocking Agents; D013973:Thyrotropin-Releasing Hormone; C044894:ethylcholine aziridinium; D012601:Scopolamine; D002794:Choline