A synthetic ceramide analog ameliorates spatial cognition deficit and stimulates biosynthesis of brain gangliosides in rats with cerebral ischemia.
A synthetic ceramide analog, L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (L-PDMP) upregulates ganglioside biosynthesis in several cell lines. In cultured cortical neurons, neurotrophic effects of L-PDMP on neurite outgrowth and synaptic activity were demonstrated. In addition, it was found that L-PDMP could ameliorate the spatial cognition deficit in rats with ischemia. To elucidate this effect, we evaluated the effect of L-PDMP on brain ganglioside biosynthesis and its therapeutic efficacy against spatial cognition deficit in rats made ischemic. Rats were trained for 2 weeks, using an 8-arm radial maze task, and then forebrain ischemia was induced. L-PDMP was injected i.p. at 40 mg/kg twice a day starting from day 1 or 3 after ischemia induction for 6 or 4 days, respectively. The first study showed significantly reduced spatial cognition deficit at 12 h after the final drug administration, and L-PDMP tended to attenuate apoptosis in hippocampal CA1. To examine the effect of L-PDMP on brain ganglioside biosynthesis, N-[3H]acetyl-D-mannosamine was infused into the lateral ventricle via an injection cannula at 12 h after the final drug administration. After 4 h, the brain gangliosides were purified and analyzed. Upregulation of ganglioside biosynthesis by L-PDMP was observed on days 3 and 5 after ischemia. These results are an indication that L-PDMP may ameliorate spatial cognition deficit by upregulating ganglioside biosynthesis in ischemic brain.
Yamagishi
Kiwamu
K
Department of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1, Nanakuma, Jonan, Fukuoka 814-80, Japan.
Mishima
Kenichi
K
Ohgami
Yusuke
Y
Iwasaki
Katsunori
K
Jimbo
Masayuki
M
Masuda
Hiroyuki
H
Igarashi
Yasuyuki
Y
Inokuchi
Jin-ichi
J
Fujiwara
Michihiro
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D002545:Brain Ischemia / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003071:Cognition / Q000187:drug effects*; D003072:Cognition Disorders / Q000209:etiology / Q000517:prevention & control; D005732:Gangliosides / Q000096:biosynthesis*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013037:Spatial Behavior / Q000187:drug effects*
D005732:Gangliosides; D009025:Morpholines; C033110:RV 538