Protective action by methylprednisolone, allopurinol and indomethacin against stroke-induced damage to adenylate cyclase in gerbil cerebral cortex.

Abstract

SUMMARY Adenylate cyclase activity was investigated in either homogenate or particulate fractions from the frontal cerebral cortex of the gerbil following five experimental conditions of bilateral ischemia. After periods of 15 min ischemia, 15 min ischemia plus 15 min of recirculation or 60 min ischemia the enzyme generally displayed enhanced responses to GTP, norepinephrine (NE), dopamine (DA), NE + GTP and DA + GTP. Pretreatment of the gerbils with methylprednisolone, allopurinol or indomethacin did not significantly influence the outcome of these findings. When the animals were subjected to 60 min ischemia plus 15 min of reflow, enzyme responses to the stimulatory agents including forskolin and NaF were all reduced. Pretreatment with methylprednisolone, allopurinol or indomethacin prevented the damage to adenylate cyclase in the 60 min ischemia plus 15 min reflow animals. When animals were made ischemic for 15 min followed by one week of recovery, enzyme sensitivity to GTP, calmodulin-Ca + + , NE, combinations thereof and forskolin were reduced in only the particulate fractions. Enzyme damage was reversed following methylprednisolone. Enzyme damage may result from generation of free radicals during reflow and drugs that either inhibit synthesis pathways generating free radicals, stabilize cell membranes or act as free radical scavengers may be therapeutically beneficial under specific conditions of stroke. Stroke Vol 15, No 2, 1984 CYCLIC NUCLEOTIDES, namely adenosine 3', 5'-monophosphate (cyclic AMP) and guanosine 3', 5'-monophosphate (cyclic GMP) appear to be involved as a consequence of traumatic insults to the brain. Thus seizures, cerebral contusion, cerebral concussions, stab wounds, anoxia and ischemia are all associated with rapid alterations in brain cyclic nucleotide levels. '" 6 With regard to ischemia, bilateral clamping of the common carotid arteries in gerbils evoked a marked rise in cerebral levels of cyclic AMP concomitant with a drop in cyclic GMP concentrations. Under conditions of reflow of blood to the brain cerebral levels of both cyclic AMP and cyclic GMP were increased. 4 The question herein was what perturbations did bilateral ischemia cause to the enzymes responsible for formation of the two cyclic nucleotides? Schwartz et al,7 demonstrated that adenylate cyclase (EC 4.6.1.1) activity did not change in gerbil cerebral cortex up to an hour after clamping one carotid artery. However, if recirculation of blood was allowed the activity of the enzyme declined up to 5 hr post-ischemia. In follow-up investigations we reported that periods of bilateral ischemia (15 min with or without 15 min reflow and 60 min -no reflow) resulted in an enhanced sensitivity of cerebral adenylate cyclase to catecholamines and GTP. However, after 60 min of bilateral ischemia followed by 15 min of recirculation neurohumoral activation of adenylate cyclase was now From the Frist-Massey Neurological Institute,

Effect of allopurinol on ischemia and reperfusion-induced cerebral injury in spontaneously hypertensive rats.

“…7 In the present study, we studied the effect of allopurinol, a xanthine oxidase inhibitor, on ischemia and reperfusion-induced cerebral injury after bilateral common carotid artery occlusion in spontaneously hypertensive rats in order to investigate the importance of xanthine oxidase-linked free radical in cerebral injury.…”

Effect of policosanol on cerebral ischemia in Mongolian gerbils

“…Among other mediators, catecholamines, serotonin, angiotensin, histamine, thrombine, thromboxane A2, leukotrienes, endothelin-1, platelet-activating factor and oxygen free radicals may participate in the development of ischemic cerebral failure (29). Cyclic nucleotides (cAMP and cGMP) appear to be involved in the consequences of traumatic insults to the brain (17). Schwartz et al (30) demonstrated that adenylate cyclase activity declines after clamping of the carotid arteries and blood recirculation restored up to 5 h post-ischemia.…”

“…Taylor et al (17) reported that adenylate cyclase damage may result from generation of free radicals during reflow in gerbils. Moreover, drugs that inhibit enzymatic processes associated with free radical formation such as allopurinol and indomethacin were effective in preventing the damage to adenylate cyclase.…”

“…On the other hand, Mongolian gerbils submitted to bilateral clamping of the common carotid arteries and recirculation develop cerebral edema in which cyclic nucleotides (cAMP and cGMP) are involved as a consequence of traumatic insults to the brain (17).…”

Hyperbaric oxygen increases survival following carotid ligation in gerbils.

“…14 Unilateral carotid artery ligation results in ipsilateral signs of stroke in approximately 50% of the animals; hence gerbils have become the subject of numerous studies. Gerbils have been used to evaluate barbiturate therapy in stroke, 15 - 16 to delineate neurotrans-and to study the effects of steroids, 18 naloxone, 19 and calcium antagonists 20 on induced cerebral ischemia. We chose the gerbil as our animal model for unilateral cerebral ischemia because of the animal's accessibility, the reproducibility of the resulting brain lesion, and the ease of animal manipulation in the HBO environment.…”