T-588, a novel neuroprotective agent, delays progression of neuromuscular dysfunction in wobbler mouse motoneuron disease.
R(-)-1-(benzo[b]thiophen-5-yl)-2-[2-(N,N-diethylamino) ethoxy]ethanol hydrochloride (T-588) enhances acetylcholine release from the frontal cortex and hippocampus in rats, and can ameliorate cognitive dysfunction in various amnesia models of rodents. T-588 protects rat cerebellar granule cells from glutamate neurotoxicity in culture. This agent also inhibits facilitation in the crayfish neuromuscular junction and mammalian cerebellum. Clinical trials of T-588 are underway in patients with Alzheimer's disease. We attempted to determine whether T-588 treatment ameliorates neuromuscular dysfunction in the wobbler mouse, an animal model of motoneuron disease (MND). After the initial diagnosis of MND at the age of 3-4 weeks, wobbler mice were orally administered T-588 (3, 10, 30 mg/kg) or vehicle daily for 4 weeks in a blinded fashion. We compared symptomatic, pathological and biochemical changes among the groups. In comparison with vehicle, T-588 administration potentiated grip strength, attenuated forelimb contracture and increased the weight of the biceps muscles. T-588-treated mice had retarded denervation muscle atrophy and elevated activities of choline acetyltransferase (ChAT) or lactate dehydrogenase in the biceps muscles. T-588 treatment also enhanced ChAT activities and promoted formation of cyclic adenosine monophosphate in the cervical cord. Pharmacokinetic study also showed that T-588 was transported efficiently into the cerebrum and spinal cord following oral administration. Thus, T-588 treatment delayed the progression of wobbler murine MND. Our findings suggest that this agent has therapeutic potential in human motor neuropathy or MND.
Ikeda
K
K
Fourth Department of Internal Medicine, Toho University Ohashi Hospital, 2-17-6, Ohashi, Meguro-ku, Tokyo, Japan.
Iwasaki
Y
Y
Kinoshita
M
M
Marubuchi
S
S
Ono
S
S
D000284:Administration, Oral; D000818:Animals; D002452:Cell Count / Q000187:drug effects; D002478:Cells, Cultured; D000697:Central Nervous System Stimulants / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004048:Diethylamines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D005552:Forelimb / Q000473:pathology / Q000503:physiopathology; D018737:Hand Strength / Q000502:physiology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D016472:Motor Neuron Disease / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D009929:Organ Size; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D013876:Thiophenes / Q000008:administration & dosage* / Q000493:pharmacokinetics
D000697:Central Nervous System Stimulants; D004048:Diethylamines; D013876:Thiophenes; C082372:T 588; D000242:Cyclic AMP; D007770:L-Lactate Dehydrogenase; D002795:Choline O-Acetyltransferase