Inhibition of NF-kappaB activation by Pyrrolidine dithiocarbamate partially attenuates hippocampal MMP-9 activation and improves cognitive deficits in streptozotocin-induced diabetic rats

Matrix metalloproteinase-9 (MMP-9) has been found at significantly increased activity and also contributes to blood–brain barrier degradation in diabetes. Activation of NF-κB pathway is associated with diabetes-induced cognitive impairment, and MMP-9 gene promoter contains a highly conserved motif that matches the NF-κB p65 binding element. No data have been yet provided to show that diabetes-induced cognitive decline is actually associated with increased activity of MMP-9, however, so we sought to understand the potential role of NF-κB-MMP-9 pathway in diabetic rats’ brain. Streptozocin (STZ) was used to induce diabetes in Wistar rats. Pyrrolidine dithiocarbamate (PDTC), an effective NF-κB inhibitor, was administrated to diabetic rats for 6 weeks from the end of diabetes induction. Six weeks later, separate cohorts of rats were tested for cognitive function with Morris water maze task, or euthanized to assess MMP-9 and NF-κB levels in hippocampus. The diabetic rats developed cognitive deficit which was associated with enhanced hippocampal MMP-9 and NF-κB expression. PDTC treatment returned the levels of NF-κB toward their control values and significantly improved diabetes-induced behavioral dysfunction. However, the hippocampal MMP-9 expression triggered by diabetes was only slightly (though significantly) attenuated because MMP-9 protein level in PDTC treated diabetic rats was still higher than that in control rats. Moreover, chronic PDTC treatment did not affect the body weight and plasma glucose levels as compared to the diabetic group, which suggested that PDTC could not ameliorate the diabetic metabolic disorder. In conclusion, these data reveal that diabetes-associated cognitive deficit stems partially from up-regulation of hippocampal MMP-9 via activation of NF-κB signaling pathway.

► Hippocampal MMP-9 up-regulation paralleled with diabetes-induced cognitive decline. ► PDTC treatment in diabetic rats returned NF-κB levels toward their control values. ► NF-κB inhibition partially attenuated the hippocampal MMP-9 expression triggered by diabetes. ► NF-κB inhibition improved diabetes-induced behavioral impairment.