Brain polyphosphoinositide metabolism during focal ischemia in rat cortex.

Abstract

Using a rat model of stroke, we examined the effects of focal cerebral ischemia on the metabolism of polyphosphoinositides by injecting "Pi into both the left and right cortices. After equilibration of the label for 2-3 hours, ischemia induced a significant decrease (p<0.001) in the concentrations of labeled phosphatidyl 4,5-bisphosphates (66-78%) and phosphatidylinositol 4-phosphate (64-67%) in the right middle cerebral artery cortex of four rats. The phospholipid labeling pattern in the left middle cerebral artery cortex, which sustained only mild ischemia and no permanent tissue damage, was not different from that of two shamoperated controls. However, when 32Pi was injected 1 hour after the ischemic insult, there was a significant decrease (p<0.01) in the incorporation of label into the phospholipids in both cortices of four ischemic rats compared with four sham-operated controls. Furthermore, differences in the phospholipid labeling pattern were observed in the left cortex compared with the sham-operated controls. The change in labeling pattern was attributed to the partial reduction in blood flow following ligation of the common carotid arteries. We provide a sensitive procedure for probing the effects of focal cerebral ischemia on the polyphosphoinositide signaling pathway in the brain, which may play an important role in the pathogenesis of tissue injury. {Stroke 1991;22:495-498)A lthough stimulation of neuronal activity, in-/ \ eluding the process of neurotransmitter re-.Z \ _ lease, is one of the early events of cerebral ischemia, 1 the mechanism leading to irreversible tissue damage is not well understood. A number of neurotransmitters are known to transduce their signals through stimulated hydrolysis of phosphatidylinositol 4,5-bisphosphates (PIFy. In turn, inositol trisphosphates can serve as second messengers for the mobilization of intracellular calcium stores.2 Therefore, stimulation of this cell signaling process may have important consequences toward explaining the alteration of calcium homeostasis underlying ischemic tissue damage.Previous studies by Ikeda et al 3 as well as those from our own laboratory 4 have indicated a rapid decrease in the levels of polyphosphoinositides (poly-PI) in rat brain after global cerebral ischemia induced by decapitation. Poly-PI were also degraded Received May 30, 1990; accepted December 13, 1990. following global cerebral ischemia induced by ligation of the common carotid arteries (CCAs) in gerbils. 5 Since these compounds are present in trace quantities in the brain, a more sensitive procedure to study the ischemia-induced breakdown of poly-PI can be achieved by prelabeling the brain with ^Pi 6 -7 or [ 3 H]inositol.8 Although the tracer technique has been used to examine poly-PI metabolism in a model of global ischemia, the response in brain tissue after a focal ischemic insult has not been examined. We used a rat model of focal cerebral ischemia to examine poly-PI metabolism after ligation of the middle cerebral artery (MCA). This model closely resembles ...

Cyanide-stimulated inositol 1,4,5-trisphosphate formation: An intracellular neurotoxic signaling cascade

“…These findings are similar to those observed with hypoxic ischemia in which intracellular IP 3 levels increased with 30-60 seconds of insult (12,14,31). The mechanism underlying the response to cyanide is not clear.…”

“…Hypoxia/ischemia activates polyphosphoinositide hydrolysis leading to formation of inositol phosphates (12)(13)(14). Phospholipase C (PLC) activation is thought to be responsible for the hypoxia-ischemiainduced polyphosphoinositide hydrolysis (15,16).…”

Alterations of local cerebral blood flow, phorbol 12,13-dibutyrate binding activity, and histological damage during acute focal ischaemia in rat brain

“…Our results regarding the relationship b e t w e e n L C B F and histological d a m a g e during the first 3 hours after M C A O began m a y support the previous observation that the striatum is m o r e vulnerable than the cortex [21,22,33]. In the assessment of the vulnerability of the neuronal cell itself, start of MCAO may indicate increase in the rate of hydrolysis of phospho-inositides into diacylglycerol and IP3 during and after ischaemia, and may also enhance PKC activity [10,19,26,41]. Tanaka et al [35] also indicated that the unilateral common carotid artery occlusion model of gerbil rats increased significantly the PDBu binding activity in the severe ischaemic area, 2 hours after initiation of occlusion.…”

Decapitation ischemia-induced release of free fatty acids in mouse brain

“…As a result of the similarity in acyl group composition between DG and phosphatidylinositol (PI), a metabolic relationship between these two types of lipids has been suggested (Keough et al, 1972). More recently, studies have provided evidence for stimulated hydrolysis of poly-phosphoinositides (poly-PI) but not PI resulting from cerebral ischemia Huang and Sun, 1986;Yoshida et al, 1986;Abe et al, 1987;Sun, 1989;Sun et al, 1988Sun et al, , 1990Lin et al, 1991). These studies further demonstrated the involvement of the bifurcating signaling system with the release of two and DG for activation of protein kinase C (Berridge, 1987).…”