geranylgeranylacetone and Ischemic-Attack--Transient

We evaluated the neuroprotective effect of geranylgeranylacetone (GGA), an antiulcer agent and inducing agent of heat-shock protein (HSP), against the delayed death of hippocampal neurons induced by transient bilateral occlusion of the common carotid artery (CCA) and hypotension (40 mm Hg) lasting for 10 min. To test the hypothesis that orally administered GGA would induce protein kinase C (PKC), leading to the expression of HSP70 and protection against delayed neuronal death (DND), we gave GGA orally to rats in various regimens prior to bilateral occlusion of the CCA, and quantitatively assessed the extent of DND in region CA1 of the hippocampus at 7 days after transient ischemia. Pretreatment with a single oral dose of GGA of 800 mg/kg at 48 h before ischemia significantly attenuated DND (20.0 +/- 3.81 vs. 321.0 +/- 11.01 mm(3); p < 0.05). A similar degree of neuron sparing occurred when GGA was given 2, 4, or 8 days before ischemia. These neuroprotective effects of GGA were prevented by pretreatment with chelerythrine (CHE), a specific inhibitor of PKC, indicating that PKC may mediate GGA-dependent protection against ischemic DND. Oral GGA-induced expression of HSP70 elicited the expression of PKCdelta, and pretreatment with GGA enhanced the ischemia-induced expression of HSP70, both of which effects were prevented by pretreatment with CHE. These results suggest that a single oral dose of GGA induces the expression of PKCdelta and promotes the expression of HSP70 in the brain, and that GGA plays an important role in neuroprotection against DND. Pretreatment with a single oral dose of GGA provides an important tool for exploring the mechanisms of neuroprotection against DND of hippocampal neurons after transient ischemia.

Topics: Animals; Cell Death; Diterpenes; Heat-Shock Proteins; Ischemic Attack, Transient; Male; Neurons; Neuroprotective Agents; Protein Kinase C; Rats; Rats, Wistar

The present study evaluated the potential effect of geranylgeranylacetone (GGA), which is known as an antiulcer agent, against the delayed neuronal death (DND) of hippocampal neurons an otherwise lethal ischemic insult. Pretreatment with single oral GGA (800 mg/kg, 2 days before ischemia) significantly attenuated DND in gerbil hippocampus. These effects of GGA were prevented by the coinjection of MK801, a noncompetitive N-methyl-d-aspartate glutamate receptor antagonist, which indicates that the protection was indeed glutamate receptor activation mediated.

Topics: Administration, Oral; Animals; Cell Death; Diterpenes; Dizocilpine Maleate; Drug Administration Schedule; Drug Antagonism; Excitatory Amino Acid Antagonists; Gerbillinae; Hippocampus; Ischemic Attack, Transient; Male; Neurons; Neuroprotective Agents; Receptors, N-Methyl-D-Aspartate; Time Factors