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.