Changes in hippocampal synapses and learning-memory abilities in a streptozotocin-treated rat model and intervention by using fasudil hydrochloride

Fasudil hydrochloride (FH), a Rho kinase inhibitor, is used to treat neurological diseases. This study aims to elucidate the anti-dementia role of FH in Alzheimer's disease. Twenty-four Sprague–Dawley rats were randomly divided into four groups: (1) sham-operated group (control), (2) sham-operated followed by FH administration group (sham+FH), (3) streptozotocin (STZ)-treated group (STZ), and (4) STZ treatment followed by FH administration group (STZ+FH). Rats in the STZ and STZ+FH groups received two divided doses of STZ (1.5 mg/kg) intracerebroventricularly on days 1 and 3, whereas control and sham+FH group rats were given citric acid/sodium citrate buffer. Rats in the sham+FH and STZ+FH groups were then treated intraperitoneally with FH (10 mg/kg) for 4 weeks, and rats in the STZ and control groups were treated with saline. Learning and memory were measured using the Morris water maze test. The synaptic ultrastructure in the CA1 region of the hippocampus was observed using electronic microscopy. The expression of synaptophysin (SYP) was measured using real-time polymerase chain reaction and western blot analyses; the expression of p-LIMK2 and p-cofilin were also detected using western blot analysis. The results indicate that STZ induced deficit in learning/memory, decrease in SYP expression, degeneration in synaptic structures, and increase in the expressions of p-LIMK2 and p-cofilin. These changes were reversed by the administration of FH, suggesting that FH has anti-dementia properties that protect synaptic structure and function. FH induced dephosphorylation (inactivation) of LIMK2 and subsequent dephosphorylation (activation) of cofilin, which may be responsible for the amelioration of neuronal synaptic structure and function.

The first study showing: ▶protective effect of fasudil hydrochloride on learning and memory in i.c.v.-STZ rats. ▶protective effect of fasudil hydrochloride on synaptic structure. ▶dephosphorylation of LIMK2 and cofilin may be involved in the process.