Elsevier

Neuroscience

Volume 200, 3 January 2012, Pages 120-129
Neuroscience

Neurodegeneration, Neuroprotection, and Disease-Oriented Neuroscience
Research Paper
Changes in hippocampal synapses and learning-memory abilities in a streptozotocin-treated rat model and intervention by using fasudil hydrochloride

https://doi.org/10.1016/j.neuroscience.2011.10.030Get rights and content

Abstract

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.

Highlights

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.

Section snippets

Animals

Male Sprague–Dawley rats weighing 250–300 g were obtained from the Experimental Animal Centre, Central South University (Hunan, China). We randomly divided the rats into four groups (n=6 in each group): (1) sham-operated group (control); (2) sham-operated followed by FH administration group (sham+FH); (3) STZ-treated group (STZ); and (4) STZ treatment followed by FH administration group (STZ+FH). After i.c.v. injection, rats were housed in groups of four per cage. They were given free access to

Changes in learning and memory in STZ rats, and the effects of FH in sham+FH and STZ+FH rats

We first analyzed the effects of FH on cognitive performance in learning and memory in sham+FH and STZ+FH rats by using the MWM test. A significant time effect (from day 1 to day 5) was found for escape latency (F[2.24, 11.2]=150.27, P<0.001). The escape latency of control rats gradually decreased from day 1 to day 5 (Fig. 1A), which is reflective of learning. During the retrieval trial conducted on day 6, control rats spent significantly more time in the target quadrant (Q4) in search of the

Discussion

The MWM test is one of the most widely accepted models for evaluation of spatial learning and memory in rodents (Morris, 1984). In this study, a gradual decrease in escape latency in the control group during the 5-day acquisition trials indicates a normal capacity for learning. The retrieval of memory is conventionally denoted by an increase in the time spent in the target quadrant and the number of times control rats crossed the target area. In contrast, the STZ group showed typical signs of

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