Induction of NADPH-diaphorase activity in the hippocampus in a rat model of cerebral ischemia and ischemic tolerance

doi:10.1016/0006-8993(94)90318-2

Brain Research

Volume 652, Issue 1, 25 July 1994, Pages 71-75

https://doi.org/10.1016/0006-8993(94)90318-2 Get rights and content

Abstract

Preconditioning of the brain with sublethal ischemia induces tolerance to subsequent lethal periods of ischemia (ischemic tolerance). In this study, we used NADPH-diaphorase histochemistry to investigate the postischemic changes of nitric oxide synthase (NOS) in the hippocampus in a rat model of cerebral ischemia and ischemic tolerance. Forebrain ischemia was induced by 4-vessel occlusion for 3 min as an ischemic preconditioning. Three days after the preconditioning or sham operation, second ischemia was induced for 6 min. A transient increase in NADPH-diaphorase activity, beginning after 2 h and maximal after 1 day, was observed in CA1 pyramidal neurons of rats subjected to 3 min of preconditioning ischemia as well as 6 min of subsequent ischemia both with and without preconditioning. In addition, expression of NADPH-diaphorase activity was seen in reactive glial cells in the damaged CA1 region of animals subjected to 6 min of ischemia without preconditioning. Thus, direct involvement of increased NADPH-diaphorase activity in ischemic tolerance was not suggested because the increased NADPH-diaphorase activity preceded the induction of ischemic tolerance which takes place 1–7 days after preconditioning. However, the present findings suggest that the induction of neuronal NADPH-diaphorase activity occurs in response to cerebral ischemia.

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Citation Excerpt :
It has been reported that S-nitrosylation occurs when NO is available at levels ranging from physiological to pathophysiology conditions [4]. Both eNOS and nNOS are expressed in hippocampal neurons and the eNOS is also distributed in hippocampal glial cells [1,2,15,22]. During the pathological process of ischemia, nNOS and eNOS in the hippocampal neurons play roles in the neuronal injures [1].
Nitric oxide (NO) plays an important role in many physiological and pathophysiological processes in the brain. In this study, we examined the mechanistic effects of an NO donor, diethylenetriamine/nitric oxide adduct (DETA/NO) on the voltage-gated calcium currents in cultured rat hippocampal neurons. DETA/NO stimulated the calcium currents and slightly increased the channel sensitivity to depolarizing voltages. The effect of DETA/NO on the calcium current was blocked by either depleting the NO in DETA/NO or by pretreating the neurons with NEM, a thiol-specific alkylating agent, suggesting an involvement of S-nitrosylation in the current response to NO. In addition, activation of the cGMP pathway by 8-Br-cGMP inhibited the calcium current in the neurons. Also, inhibition of guanylyl cyclase by 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ) increased the current response to DETA/NO. Taken together, our results demonstrate that both S-nitrosylation and cGMP pathway are involved in the NO modulation of the hippocampal calcium current.
Ischemic preconditioning-induced activation of ERK1/2 in the rat hippocampus
2006, Neuroscience Letters
We investigated the activation and cellular localization of the extracellular signal-regulated kinases ERK1/2 in a rat model of ischemic tolerance induction. Adult male Sprague–Dawley rats were subjected to 3 min of sublethal ischemic preconditioning. Activation of ERK1/2 showed the characteristic time- and cell-dependent patterns. Rapid and short-lasting activation of ERK after 3 min of cerebral ischemia was noted immediately in the dentate granule cells and mossy fibers of the hippocampus, and then occurred sequentially in CA3 and CA1 neurons and dentate hilar neurons at 10 min. Phosphorylation of ERK1/2 in hippocampal neurons returned to the basal level in an ordered manner. Basal level phosphorylation was attained first, at 30 min, by the CA1 neurons, and was then observed in CA3 and granule cells by 1 h and noted in some dentate hilar neurons at 12 h. By contrast, phosphorylation of ERK1/2 in mossy fibers and the CA1 dendritic field was sustained for at least 3 d. Transient activation of ERK1/2 was induced also in astrocytes of the dentate hilar region at 1 d post-stimulation. These data demonstrate that the short cerebral-ischemic preconditioning induced rapid and transient activation of ERK1/2 in tolerance-acquired CA1 neurons as well as in ischemia-resistant CA3 and dentate granule cells, and that the short preconditioning sustained activation in mossy fibers and neuropil areas, suggesting that ERK1/2 activation may be involved in the mechanism of ischemic tolerance in the rat hippocampus.
Dynamic changes in CA1 dendritic spines associated with ischemic tolerance
2006, Experimental Neurology
Hippocampal CA1 neurons are particularly vulnerable to 5–10 min durations of global ischemia. These cells can develop tolerance to ischemia through prior exposure to brief episodes of ischemia (ischemic preconditioning, IP). Dendritic spines are implicated in various forms of neuroplasticity including memory and recovery of function. Here we characterized the changes in hippocampal CA1 dendritic spines during the development of ischemic tolerance and the subsequent postischemic recovery period. Gerbils received 5 min, bilateral carotid artery occlusions preceded by two 1.5 min occlusions each of which were 24 h apart (tolerance groups). Spine densities were calculated from CA1 apical and basilar dendrites in tolerant animals that survived 3 (IP3), 10 (IP10) or 30 (IP30) days as well as sham-operated animals and those that received only the two preconditioning episodes (PO). Habituation to a novel open-field was assessed 3, 7, 10 and 30 days after ischemia to gauge CA1 functional integrity. Dendritic spines were quantified from Golgi-Cox stained sections of the CA1 subfield. IP10, IP30 and PO animals had significantly higher CA1 basilar and apical spine densities than all other groups. Tolerant animals initially displayed open-field habituation impairments at a time when spine densities were reduced. Behavioral impairments gradually subsided over time in coincidence with an increase in CA1 spine densities. These findings suggest that dendritic spines may play a role in recovery of function associated with ischemic tolerance and stroke.
Ischemic preconditioning-induced expression of gp130 and STAT3 in astrocytes of the rat hippocampus
2004, Molecular Brain Research
We investigated the distribution and time course of expression of both gp130 mRNA and signal transducer and activator of transcription factor-3 (STAT3) in a rat model of ischemic tolerance induction. Forebrain ischemia was induced by four-vessel occlusion for 3 min as an ischemic preconditioning. Ischemic preconditioning 3 days before a 10-min lethal ischemia preserved neuronal signal. Expression of gp130 mRNA was induced 12 h after ischemic preconditioning, and was most prominent in the CA1 and the hilar region at 3 days, with expression sustained for at least 7 days. Ischemic preconditioning-induced STAT3 activation, as revealed by nuclear translocation, resembled that of gp130 expression. Nuclear STAT3 immunoreactivity occurred in the CA1 and the hilar region within 12 h after ischemic preconditioning, and was sustained for at least 7 days. Double-labeling experiments revealed that the cells expressing gp130 or STAT3 were glial fibrillary acidic protein (GFAP) immunoreactive astrocytes. These results demonstrate upregulation of gp130 and STAT3 in reactive astrocytes following ischemic preconditioning, indicating that this signal pathway is involved in the astroglial reaction to ischemic preconditioning in the rat hippocampus.
Different strains of rats show different sensitivity to block of long-term potentiation by nitric oxide synthase inhibitors
2002, European Journal of Pharmacology
Nitric oxide is presumed to play important roles in the induction of synaptic plasticity and learning. Previous publications, however, reported contradictory results. Block of nitric oxide synthase (NOS) has been shown to impair the induction of long-term potentiation of synaptic transmission in some studies. Other studies observed a partial block of long-term potentiation depending on experimental conditions, while yet other studies did not find an effect of NOS inhibitors under any conditions tested. Some reasons for these differences had been identified, e.g. the temperature of the slice buffer, the age of the animals, and the specific stimulation protocols used. Still, even when taking these parameters into account, not all results can be explained. The present study compares three strains of rats and observes large differences in sensitivity to nitric oxide synthase (NOS) blockers on the induction of long-term potentiation. While Wistar rats showed an almost complete block of long-term potentiation when using the NOS inhibitors 7-nitro-indazole (30 mg/kg ip) or 1-(2-trifluoromethylphenyl) imidazole (TRIM; 150 nmol/5 μl icv), 117±5 S.E.M. of % of baseline slope values of excitatory postsynaptic potentials. Sprague–Dawley and Long–Evans rats showed no or only weak effects of drugs on the induction of long-term potentiation (166±17 S.E.M. of % of baseline slopes in Sprague–Dawley rats, 173±24 S.E.M. of % of baseline values in Long–Evans rats). The results could explain at least some of the discrepancies of the efficacy of NOS inhibitors on synaptic plasticity that is found in the literature. Such large strain differences suggest that results from studies that use laboratory rats could have strain-dependent components and should be generalised cautiously.
Aminoguanidine prevented the impairment of learning behavior and hippocampal long-term potentiation following transient cerebral ischemia
2001, Behavioural Brain Research
The present study was performed to investigate whether increases in nitric oxide (NO) production via inducible nitric oxide synthase (iNOS) were involved in impairment of learning behavior and hippocampal long-term potentiation (LTP) following transient ischemia. Rats with four-vessel occlusion (4-VO) were used as an ischemic model. One week after permanent occlusion of the vertebral arteries, the common carotid arteries were clamped for 10 min under halothane anesthesia. Aminoguanidine (10 mg/kg i.p.), a relatively selective iNOS inhibitor, or saline was administered 30 min before common carotid arteries occlusion, and every 24-h for 4 days. We investigated whether hippocampal NO production was increased by ischemic insult using microdialysis on days 1, 4 and 7 after 4-VO. On days 1 and 4 after 4-VO, increases in NO production were observed, and this effect was inhibited by aminoguanidine. Four days after 4-VO, rats were subjected to the Y-maze test and contextual fear conditioning. Ischemic insults impaired learning behavior, and aminoguanidine ameliorated the impairment induced by 4-VO. Four days after 4-VO, the changes in the population spike amplitude were recorded as an index of LTP in Schaffer collateral–CA1 (carotid artery 1), the mossy fiber–CA3 and the perforant path–dentate gyrus synapses. LTP was significantly inhibited by 4-VO, except in mossy fiber–CA3 synapses. Pretreatment with aminoguanidine prevented the reduction of LTP in perforant path–dentate gyrus, but not in Schaffer collateral–CA1 synapses. These results suggest that post-ischemic increase in NO production via iNOS impaired the learning behavior. There is an association between behavioral performance and LTP formation in perforant path–dentate gyrus synapses, but neither in Schaffer collateral–CA1 nor in mossy fiber–CA3 synapses.

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Induction of NADPH-diaphorase activity in the hippocampus in a rat model of cerebral ischemia and ischemic tolerance

Abstract

Brain Res.

Neuron

Neuron

Brain Res. Bull.

Brain Res.

Brain Res.

Neuroscience

Cell

Brain Res.

Neuroscience

Neuroscience

Nitric oxide synthase and neuronal NADPH diaphorase are identical in brain and peripheral tissues