A synthetic ceramide analog ameliorates spatial cognition deficit and stimulates biosynthesis of brain gangliosides in rats with cerebral ischemia

Abstract

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.