Intraischemic but not postischemic hypothermia prevents non-selective hippocampal downregulation of AMPA and NMDA receptor gene expression after global ischemia

Hypothermia may afford histological neuroprotection induced by ischemia by preventing aberrant Ca2+ influx through NMDA (N-methyl-d-aspartic acid) or Ca2+-permeable AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) receptors. Expression of hippocampal GluR1(A), GluR2(B), GluR3(C) and NMDAR1 (NR1) subunits was investigated by in situ hybridization at 1 and 7 days after 10-min transient global ischemia in the presence and absence of intraischemic or postischemic brain hypothermia (30°C). At 1 day, normothermic ischemia markedly suppressed the expression of GluR1(A), GluR2(B), and GluR3(C) receptor mRNAs to a similar degree in the vulnerable CA1. Less vulnerable CA3a–c subregions were also acutely downregulated. NR1 mRNA expression was reduced in CA1 but to a lesser extent than AMPA mRNAs. At 7 days after normothermic ischemia, a time of marked CA1 cell loss, all three AMPA transcripts were nearly absent in CA1 while a percentage (33.9±7.2%) of NR1 mRNA remained. Intraischemic hypothermia fully blocked the damage and non-selective mRNA downregulations at 1 and 7 days. By contrast, postischemic hypothermia postponed neurodegeneration but only partially rescued the expression of AMPA and NR1 mRNAs at 7 days and not at 1 day after the insult. Therefore, hippocampal AMPA receptor mRNAs decline at a relatively similar rate after normothermic global ischemia and cellular neuroprotection by intraischemic hypothermia occurred independently of altered subunit composition of AMPA receptors. Since decreases persist within resistant neurons under the postischemic condition, AMPA receptor-mediated Ca2+ currents probably do not contribute to selective vulnerability

Combined postischemic hypothermia and delayed MK-801 treatment attenuates neurobehavioral deficits associated with transient global ischemia in rats

The present study was designed to determine whether postischemic hypothermia, delayed MK-801 (dizocilpine) administration, or a combination of these treatments can provide lasting neurobehavioral protection following transient global ischemia in rats. Rats were subjected to 10 min of normothermic (37°C) ischemia induced by 2-vessel occlusion and hypotension (50 mmHg) or sham procedures. Ischemia was followed by either: (a) 3 h at normothermic brain temperatures, (b) 3 h of postischemic brain hypothermia at 30°C, (c) hypothermia coupled with MK-801 (4 mg/kg, i.p.) on postischemic days 3, 5 and 7, or (d) postischemic MK-801 treatment alone. Neurobehavioral evaluation 6–8 weeks following surgery showed that normothermic ischemia (NI) was associated with water maze navigational deficits, including performance on a simple place task involving finding a hidden platform maintained in one position for 6 days, and a learning set task in which the platform was moved to a different location each day (both P's< 0.02 vs. sham). NI was also associated with increased locomotion in an open field ( P < 0.01 vs. sham). A combination of postischemic hypothermia and delayed MK-801 injections provided partial protection from ischemic-associated hyperactivity in the open field ( P < 0.02 vs. NI), and robust protection from simple place task deficits ( P < 0.02 vs. NI). Evidence for significant protective effects of MK-801 or hypothermia alone was observed in the learning set, during the final trial blocks each day. These results provide further evidence for neuroprotective effects of these treatments at chronic survival intervals, and indicate that the therapeutic window for attenuating ischemic damage is considerably longer than has heretofore been appreciated

Feed-forward excitation of striatal neuron activity by frontal cortical activation of nitric oxide signaling in vivo

The gaseous neurotransmitter nitric oxide plays an important role in the modulation of corticostriatal synaptic transmission. This study examined the impact of frontal cortex stimulation on striatal nitric oxide efflux and neuron activity in urethane-anesthetized rats using amperometric microsensor and single-unit extracellular recordings, respectively. Systemic administration of the neuronal nitric oxide synthase inhibitor 7-nitroindazole decreased spontaneous spike activity without affecting activity evoked by single-pulse stimulation of the ipsilateral cortex. Train (30 Hz) stimulation of the contralateral frontal cortex transiently increased nitric oxide efflux in a robust and reproducible manner. Evoked nitric oxide efflux was attenuated by systemic administration of 7-nitroindazole and the non-selective nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester. Train stimulation of the contralateral cortex, in a manner identical to that used to evoke nitric oxide efflux, had variable effects on spike activity assessed during the train stimulation trial, but induced a short-term depression of cortically evoked activity in the first post-train stimulation trial. Interestingly, 7-nitroindazole potently decreased cortically evoked activity recorded during the train stimulation trial. Moreover, the short-term depression of spike activity induced by train stimulation was enhanced following pretreatment with 7-nitroindazole and attenuated after systemic administration of the dopamine D2 receptor antagonist eticlopride. These results demonstrate that robust activation of frontal cortical afferents in the intact animal activates a powerful nitric oxide-mediated feed-forward excitation which partially offsets concurrent D2 receptor-mediated short-term inhibitory influences on striatal neuron activity. Thus, nitric oxide signaling is likely to play an important role in the integration of corticostriatal sensorimotor information in striatal networks