Immunohistochemical investigation of caspase-1 and effect of caspase-1 inhibitor in delayed neuronal death after transient cerebral ischemia

The localization of caspase-1 protein, interleukin-1 beta (IL-1 beta)-conve rting enzyme, was immunohistochemically examined in the hippocampal CA-1 su bfield by a transient occlusion of bilateral common carotid arteries in Mon golian gerbils. Immunoreactivities for caspase-1 were found in microglias, astrocytes, endothelial cells of capillaries and some non-pyramidal neurons . Immunopositive microglias increased in number from 3 days until 7 days fr om the transient ischemia, and astrocytes also increased in number from 3 d ays until 28 days. At the electron microscopic level, caspase-1 immunoreact ion endproducts were associated with Golgi apparatus in glial cells, endoth elial cells of blood vessels and non-pyramidal neurons. The delayed neurona l death of CA-1 pyramidal cells was significantly protected by the treatmen t of specific caspase-1 inhibitor (Ac-WEHD-CHO) or broad caspase family inh ibitor (z-VAD-FMK). Cell death was protected in a dose dependent manner by the former by 43-57%, and by the latter by 66-91% when injected at 1 and 10 mug, respectively. On the other hand, the protective effect of specific ca spase-3 inhibitor (Ac-DMQD- CHO) was less significant at higher dose (10 mu g) by 33% (P<0.05), and not detectable at lower dose (I <mu>g) by 13% (P=0. 27). Furthermore, a significant decrease of microglias and astrocytes was f ound in the CA-1 as well as the reduction of IL-1 beta and caspase-1 immuno reactivities by the treatment of Ac-WEHD-CHO. Extravasation of serum albumi n was also extremely reduced by this treatment. These findings suggest that the inhibition of caspase-1 activity ameliorates the ischemic injury by in hibiting the activity of IL-1 beta. (C) 2001 Elsevier Science B.V. All righ ts reserved.