Pyrrolidine dithiocarbamate attenuates brain Aß increase and improves long-term neurological outcome in rats after transient focal brain ischemia.

ABSTRACT

Evidence suggests an association between brain ischemia and Alzheimer's disease (AD) development. Amyloid plaques consisted of ß-amyloid peptide (Aß) in the brain are a pathological hallmark of AD. Little is known about how brain ischemia induces AD-like neuropathology. A strategy effective to block such brain changes has not been reported. Here, adult male Sprague-Dawley rats were subjected to a 90-min right middle cerebral artery occlusion (MCAO). Pyrrolidine dithiocarbamate (PDTC) at various doses was given daily via gastric gavage with the first dose given at 10 min after the onset of reperfusion. The MCAO increased Aß1-42 concentrations in the ischemic brain tissues. PDTC attenuated this increase. PDTC also decreased the ischemia-reduced expression of neprilysin, an Aß degrading enzyme. Aß1-42 levels were negatively correlated with neprilysin protein abundance. Brain ischemia decreased the expression of ß-amyloid converting enzyme 1, a key enzyme to produce Aß, and increased the expression of insulin-degrading enzyme, another Aß degrading enzyme. Animals had impaired learning and memory at 2 months after the MCAO. PDTC attenuated this impairment. PDTC also improved long-term neurological outcomes. Our findings suggest that PDTC improves long-term neurological outcome of rats after transient focal brain ischemia. PDTC reduces ischemia-induced Aß accumulation, possibly via preserving neprilysin expression.