Protective effects of SR 57746A in central and peripheral models of neurodegenerative disorders in rodents and primates.
Compounds possessing neurotrophic properties may represent a possible treatment for neurodegenerative disorders such as Alzheimer's disease. SR 57746A, 1-[2-(naphth-2-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,5,6- tetrahydropyridine hydrochloride, is a new compound with neurotrophic activity in a number of in vitro preparations. The neurotrophic effects of this compound have been evaluated in vivo using four distinct rat models of neurodegeneration: transient global ischaemia produced by a four-vessel occlusion; septohippocampal lesion produced by injection of vincristine sulphate into the medial septum; sciatic nerve crushing; and acrylamide-induced peripheral neuropathy. Rats were administered vehicle or 2.5-10 mg/kg p.o. SR 57746A, after initiation of the degenerative process, then once daily for 10 days in the first two models, 16 days in the third and 26 days in the fourth model. Median scores for ischaemia-induced neuronal damage were reduced by 30-40% by SR 57746A treatment in hippocampal CA1, CA2, and CA3 regions, and in the dorsal striatum. Twelve days after intraseptal vincristine administration, there was a marked loss of septohippocampal cholinergic neurons, as indicated by reduced choline acetyltransferase activity in both the septum and hippocampus. SR 57746A dose-dependently reversed this reduction in both areas. These results were confirmed by histoenzymological evaluation of hippocampal acetylcholinesterase content. SR 57746A also reversed the loss of hippocampal choline acetyltransferase induced by intraseptal vincristine in marmosets. Behavioral deficits in these models (exploratory behaviour in the former and short-term social memory in the latter) were also significantly reduced by SR 57746A treatment. In the sciatic crush model, sensorimotor function improved more rapidly in rats treated with 10 mg/kg SR 57746A. In this same model, SR 57746A (10 mg/kg/day) also significantly increased the length of regenerated nerve eight days after the crush, as measured using the pinch test. Finally, SR 57746A retarded the onset, reduced the amplitude and accelerated the recovery of acrylamide-induced peripheral neuropathy. Thus, SR 57746A possesses notable neurotrophic activity in a variety of neurodegenerative models in vivo, suggesting that the compound may possess therapeutic potential for the treatment of neurodegenerative diseases.
Fournier
J
J
Sanofi Recherche, Toulouse, France.
Steinberg
R
R
Gauthier
T
T
Keane
P E
PE
Guzzi
U
U
Coudé
F X
FX
Bougault
I
I
Maffrand
J P
JP
Soubrié
P
P
Le Fur
G
G
D000110:Acetylcholinesterase / Q000032:analysis; D020106:Acrylamide; D000178:Acrylamides / Q000633:toxicity; D000818:Animals; D015415:Biomarkers; D002545:Brain Ischemia / Q000188:drug therapy / Q000503:physiopathology; D002144:Callithrix; D002795:Choline O-Acetyltransferase / Q000032:analysis; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology; D009409:Nerve Crush; D009410:Nerve Degeneration / Q000187:drug effects*; D009414:Nerve Growth Factors / Q000494:pharmacology; D009416:Nerve Regeneration; D009419:Nerve Tissue Proteins / Q000032:analysis; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control; D011597:Psychomotor Performance / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000145:classification / Q000187:drug effects / Q000502:physiology; D012584:Sciatic Nerve / Q000293:injuries / Q000502:physiology; D012688:Septum Pellucidum / Q000187:drug effects / Q000502:physiology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013045:Species Specificity; D014750:Vincristine / Q000633:toxicity
D000178:Acrylamides; D015415:Biomarkers; D009281:Naphthalenes; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D011725:Pyridines; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D020106:Acrylamide; D014750:Vincristine; D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase; C462299:xaliproden