Lithium, phenserine, memantine and pioglitazone reverse memory deficit and restore phospho-GSK3β decreased in hippocampus in intracerebroventricular streptozotocin induced memory deficit model

Intracerebroventricular (ICV) streptozotocin (STZ) treated rat has been described as a suitable model for sporadic Alzheimer's disease (AD). Central application of STZ has demonstrated behavioral and neurochemical features that resembled those found in human AD. Chronic treatments with antioxidants, acetylcholinesterase (AChE) inhibitors, or improving glucose utilization drugs have reported a beneficial effect in ICV STZ-treated rats. In the present study the post-training administration of a glycogen synthase kinase (GSK3) inhibitor, lithium; antidementia drugs: phenserine and memantine, and insulin sensitizer, pioglitazone on memory function of ICV STZ-rats was assessed. In these same animals the phosphorylated GSK3 beta (p-GSK3 beta) and total GSK3 beta levels were determined, and importantly GSK3 beta regulates the tau phosphorylation responsible for neurofibrillary tangle formation in AD. Wistar rats received ICV STZ application (3 mg/kg twice) and 2 weeks later short- (STM) and long-term memories (LTM) were assessed in an autoshaping learning task. Animals were sacrificed immediately following the last autoshaping session, their brains removed and dissected. The enzymes were measured in the hippocampus and prefrontal cortex (PEG) by western blot. ICV STZ-treated rats showed a memory deficit and significantly decreased p-GSK3 beta levels, while total GSK3 beta did not change, in both the hippocampus and PFC. Memory impairment was reversed by lithium (100 mg/kg), phenserine (1 mg/kg), memantine (5 mg/kg) and pioglitazone (30 mg/kg). The p-GSK3 beta levels were restored by lithium, phenserine and pioglitazone in the hippocampus, and restored by lithium in the PFC. Memantine produced no changes in p-GSK3 beta levels in neither the hippocampus nor PFC. Total GSK3 beta levels did not change with either drug. Altogether these results show the beneficial effects of drugs with different mechanisms of actions on memory impairment induced by ICV STZ, and restored p-GSK3 beta levels, a kinase key of signaling cascade of insulin receptor. (C) 2011 Elsevier BAT. All rights reserved.