inosine-triphosphate and Brain-Ischemia

Receptor autoradiographic and histological techniques were used to investigate the long-term changes that occur in the gerbil brain following the induction of transient cerebral ischemia. Transient ischemia was induced for 3 and 10 min, and animals were allowed to survive for eight months. Autoradiographic analysis of second messenger systems showed that 3-min ischemia caused a significant reduction in [3H]inositol-1,4,5-trisphosphate binding in the hippocampal CA1 sector, whereas the alteration in [3H]phorbol 12,13-dibutyrate, [3H]forskolin and [3H] cyclic-AMP bindings was not found in this region. In the striatum, 3-min ischemia caused no significant alteration in [3H]phorbol 12,13-dibutyrate, [3H]inositol-1,4,5-trisphosphate and [3H]forskolin binding sites, whereas the [3H]cyclic-AMP binding showed a significant elevation. The thalamus exhibited a significant elevation only in the [3H]inositol-1,4,5-trisphosphate binding sites. Following 10-min ischemia, [3H]phorbol 12,13-dibutyrate, [3H]inositol-1,4,5-trisphosphate and [3H]cyclic-AMP binding sites revealed a significant reduction in the hippocampus, whereas the [3H]forskolin binding showed a significant elevation in this area. In the striatum, 10-min ischemia caused no significant alteration in [3H]phorbol 12,13-dibutyrate, [3H]inositol-1,4,5-trisphosphate and [3H]cyclic-AMP binding sites. However, marked reduction in the [3H]forskolin binding was seen in the striatum. Furthermore, the substantia nigra also exhibited a significant reduction in [3H]forskolin binding. Histological studies suggested that 3-min ischemia can produce severe neuronal damage and mild shrinkage to the hippocampal CA1 sector. They also showed that 10-min ischemia can cause severe tissue shrinkage and severe neuronal damage in the hippocampal CA1 sector and hippocampal CA3 sector. Thus, the hippocampal damage following ischemia was not static but progressive.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Autoradiography; Brain Chemistry; Brain Ischemia; Colforsin; Cyclic AMP; Gerbillinae; Inosine Triphosphate; Male; Phorbol 12,13-Dibutyrate; Protein Kinase C; Second Messenger Systems

Preconditioning the brain with sublethal ischemia protects against neuronal damage following subsequent ischemic insult. Using [3H]inositol 1,4,5-triphosphate (IP3), [3H]phorbol 12,13-dibutyrate (PDBu), [3H]cyclic adenosine monophosphate (cAMP) and [3H]rolipram, we performed quantitative autoradiography to determine postischemic alterations in second-messenger systems in the gerbil hippocampus following preconditioning the brain with sublethal ischemia. At 7 days of reperfusion, no alterations were observed in brains subjected to 2 min of forebrain ischemia which produced no neuronal damage. However, 3-min ischemia caused a 75% reduction in [3H]IP3 binding (p < 0.01 vs. control) and 15-25% reductions in [3H]forskolin (p < 0.01 vs. control), [3H]cAMP (p < 0.05 vs. control), and [3H]rolipram (p < 0.01 vs. control) binding in the CA1 subfield coincident with histopathological CA1 pyramidal cell destruction, but no significant alterations in [3H]PDBu binding. Preconditioning the brain with 2 min of ischemia followed by 4 days of reperfusion prevented both histopathological cell death and the reductions in binding following subsequent 3 min of ischemia. Interestingly, [3H]IP3 and [3H]rolipram binding in CA1 showed a transient reduction, by 30% and 20% (both p < 0.01 vs. control), respectively, in the early reperfusion period. This downregulation of the IP3 system may play a role in the protection against cell death.

Topics: Animals; Autoradiography; Brain Ischemia; Colforsin; Cyclic AMP; Gerbillinae; Hippocampus; Inosine Triphosphate; Male; Phorbol 12,13-Dibutyrate; Phosphodiesterase Inhibitors; Protein Kinases; Pyrrolidinones; Rolipram; Second Messenger Systems

We studied the alterations of calcium accumulation and intracellular signal transduction using autoradiography of the second messenger system in order to clarify the mechanisms of the delayed neuronal changes in the remote areas of rat brain after transient focal ischemia. Chronological changes of 45Ca accumulation and [3H]inositol 1,4,5-trisphosphate (IP3) binding sites were determined after 90 min of right middle cerebral artery (MCA) occlusion and after such occlusion followed by different periods of recirculation. After the ischemic insult, 45Ca accumulation extended to the lateral segment of the caudate putamen and to the cerebral cortex, both supplied by the occluded MCA. One day after the ischemia, [3H]IP3 binding sites decreased significantly compared with the control values in these ischemic areas. Moreover, 3 days after the ischemia, 45Ca accumulation was first detected in the ipsilateral thalamus and the substantia nigra, which lay outside the ischemic areas. In the substantia nigra, a significant decrease of [3H]IP3 binding sites and concurrent 45Ca accumulation were observed. In the thalamus, however, there was not alteration until 1 week after the ischemia, and then [3H]IP3 binding sites increased significantly 2 weeks (P less than 0.05) and 4 weeks (P less than 0.01) after the ischemia. Based on the present study, we speculate that different mechanisms associated with signal transduction systems may be responsible for exo-focal postischemic delayed neuronal changes in the thalamus and the substantia nigra. The increase of [3H]IP3 binding sites of the thalamus in the chronic stage may be new evidence of plasticity related to neurotransmission.

Topics: Animals; Autoradiography; Brain; Brain Chemistry; Brain Ischemia; Calcium; Calcium Radioisotopes; Cerebral Arteries; Inosine Triphosphate; Male; Rats; Rats, Inbred Strains; Signal Transduction

Chronological changes of [3H]inositol 1,4,5-trisphosphate (IP3) binding sites were determined after 90 min of right middle cerebral artery (MCA) occlusion and after such occlusion followed by different periods of recirculation. One day after the ischemia, [3H]IP3 binding sites decreased significantly compared with the control values in the lateral segment of the caudate putamen and the cerebral cortex, both supplied by the occluded MCA. Moreover, 3 days after the ischemia, a significant decrease of [3H]IP3 binding sites was observed in the substantia nigra of ischemic side. In the ipsilateral thalamus, however, there was no alteration until 1 week after the ischemia, and then [3H]IP3 binding sites increased significantly 2 weeks (P less than 0.05) and 4 weeks (P less than 0.01) after the ischemia. Based on the present study, we speculate that different mechanisms associated with signal transduction systems may be responsible for exo-focal postischemic delayed neuronal changes in the thalamus and the substantia nigra. The increase of [3H]IP3 binding sites of the thalamus in the chronic stage may be new evidence of plasticity related to neurotransmission.

Topics: Animals; Autoradiography; Brain; Brain Chemistry; Brain Ischemia; Calcium Radioisotopes; Caudate Nucleus; Cerebral Arteries; Inosine Triphosphate; Male; Putamen; Rats; Rats, Inbred Strains; Reperfusion; Second Messenger Systems; Signal Transduction; Substantia Nigra; Thalamus

A quantitative autoradiographic study was made on the binding of the phosphatidylinositol system ligand [3H]inositol(1,4,5)-trisphosphate (IP3) to forebrain sections from rats decapitated various times after 10 min of forebrain ischemia. To investigate the effect of a deafferentation of the hippocampal CA1, kainic acid-induced CA3-lesioned rats with or without 10 min of cerebral ischemia, were also included. The highest binding was found in the hippocampal CA1. Ten min of cerebral ischemia did not change the binding significantly. Between 5 min and 1 h of recirculation there was a 25-35% binding decline in all regions. In the CA1, where the pyramidal cells became necrotic 6 days after ischemia, there was a further decline to 16% of control. In the cortex, where there is no necrosis in this model, binding did not return to control values until day 14. Four days after a selective CA3 lesion with kainic acid, there was a significant 25% decline in the cortex, dentate gyrus and CA1, whereas in the necrotic CA3 binding declined to 54% of control. Ten min of ischemia did not alter this binding significantly. This decrease in calcium mobilizing intracellular receptors after ischemia and seizures could be due to increased membrane degradation, or to a more specific down-regulation following increased intracellular concentration of calcium and IP3.

Topics: Animals; Autoradiography; Brain Ischemia; Calcium; Hippocampus; Inosine Triphosphate; Kainic Acid; Male; Pyramidal Tracts; Rats; Rats, Inbred Strains