Protective Effect of GTS-21, a Novel Nicotinic Receptor Agonist, on Delayed Neuronal Death Induced by Ischemia in Gerbils

Abstract

The neuroprotective effects of GTS-21 [3-(2,4-dimethoxybenzylidene)-anabaseine dihydrochloride] were studied and compared with those of nicotine, 9-amino-1,2,3,4-tetrahydroacridine hydrochloride hydrate (THA) and pentobarbital-Na (PB) using a cerebral ischemia model in Mongolian gerbils. The learning performance and memory retention were elucidated by a step-through passive avoidance task at 2 and 3 days after ischemia-reperfusion. In this task, the ischemia-operated gerbils showed impairment of learning performance and memory retention. Neuronal cell death in the hippocampal CA1 area was observed at 7 days after ischemia. When administered i.p. 30 min before ischemia, GTS-21 (5 mg/kg), (-)-nicotine (1.5 mg/kg), THA (5 mg/kg) and PB (50 mg/kg) significantly attenuated the impairment of passive avoidance performance and the neuronal cell death induced by the ischemia. When administered orally twice daily for 2 weeks prior to the ischemia, GTS-21 (10 mg/kg) significantly suppressed both amnesia and neuronal cell death, while (-)-nicotine (10 mg/kg) and THA (10 mg/kg) suppressed only the amnesia. These results suggest that GTS-21 exerts a protective activity on not only impairment of learning and memory but also delayed neuronal death and that the underlying mechanism of GTS-21 differs from that of nicotine or THA.

Preventive Effect of Chotosan, a Kampo Medicine, on Transient Ischemia-Induced Learning Deficit Is Mediated by Stimulation of Muscarinic M1 But Not Nicotinic Receptor

“…3C). Similarly, the effect of tacrine on water maze performance of T2VO mice was inhibited by co-administration of pirenzepine [F treatment (1,16)ϭ28.700, pϽ0.001] (Fig. 3E) (Figs.…”

“…1B). Pretreatment of T2VO mice with tacrine, a cholinesterase inhibitor, significantly prolonged swimming time in the target quadrant [F (1,16) On the other hand, pretreatment with Uncaria-free chotosan had no effect on learning performance of T2VO mice in the training test [F treatment (1,17) (Fig. 2B), whereas Uncaria extract, when given at the doses which were approximately equivalent to the amount of this herb included in chotosan, dose-dependently reduced the escape latency in the training test [F treatment (2,27)ϭ7.116, pϽ0.01] and prolonged the swimming time in the target quadrant (pϽ0.05) (Figs.…”

“…15) Moreover, stimulation of nicotinic a7 receptors reportedly shows a similar protective effect on ischemia-induced neuronal injury. 16) Thus, cholinergic tone may play an important role in the protection from ischemic injury. In the present study, we investigated whether chotosan exerts a protective effect on ischemia-induced insults through cholinergic systems.…”

Molecular Physiology of Preconditioning-Induced Brain Tolerance to Ischemia

“…2) The selective partial ␣7-agonist 3-(2,4-dimethoxybenzylidene)-anabaseine dihydrochloride (GTS-21) protected hippocampal CA1 neurons against delayed cell death produced by transient global brain ischemia in gerbils (275); the acetylcholinesterase inhibitor donepezil reduced the infarct volume produced by MCAO in rats, and this effect was prevented by the nAChR antagonist mecamylamine (122).…”

Treating schizophrenia symptoms with an α7 nicotinic agonist, from mice to men

“…DMXBA improves one-way active avoidance, Lashley III maze testing, and 17 arm radial maze test performance in aged rats [113,114]. Passive avoidance deficits are normalized in rats [115] and ischemia-induced hippocampal cell death and impaired passive avoidance performance in gerbils are prevented by treatment with DMXBA [116]. DMXBA also improves performance on the Morris water maze [117].…”