cyclic-gmp and Cerebral-Infarction

This study is to investigate the effect of gamma-hydroxybutyric acid receptor (GHBR) on focal cerebral ischemia-reperfusion injury in rats and its mechanism. NCS-356 (the agonist of GHBR) and NCS-382 (the antagonist of GHBR) were adopted as the tool medicine. The ripe male Sprague-Dawley rats weighing 240 - 280 g were randomly divided into seven groups: sham operation group (sham), ischemia-reperfusion group (Isc/R), NCS-356 160 microg x kg(-1) group (N1), NCS-356 320 microg x kg(-1) group (N2), NCS-356 640 microg x kg(-1) group (N3), NCS-382 640 microg x kg(-1) + NCS-356 640 microg x kg(-1) group (NCS-382 + N3), and nimodipine (Nim) 600 microg x kg(-1) group. The middle cerebral artery occlusion (MCAO) model referring to Longa's method with modifications was adopted. The effect of GHBR on behavioral consequence of MCAO rats was studied after 2 h of ischemia-reperfusion. After 24 h of ischemia-reperfusion, part of animals were used to measure the cerebral infarction volume by TTC staining; ischemic cortex of another part of animals were used to measure the content of intracellular free calcium by flow cytometry, the tNOS, iNOS activity and the content of NO by spectrophotometric method, the content of cGMP by radioimmunoassay. The neurological function score and infarction volume rate in Isc/R group rats increased significantly than that in sham group; The content of intracellular calcium ([Ca2+]) of cortex neuron and cGMP, the activities of tNOS and iNOS, and the content of NO in Isc/R group were higher than that in sham group obviously (P < 0.01); These consequence we mentioned of N1, N2, N3 and Nim group were lower than that of Isc/R. NCS-382 + N3 group could significantly antagonize the above effect of N3. Thus, NCS-356 has protective effects against ischemia-reperfusion brain injury by activating GHBR. The neuroprotective effect of GHBR is related with decreasing the content of [Ca2+]i, NO, cGMP and tNOS, iNOS activity in MCAO rats.

Topics: Animals; Benzocycloheptenes; Calcium; Cerebral Cortex; Cerebral Infarction; Cyclic GMP; Infarction, Middle Cerebral Artery; Male; Neuroprotective Agents; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface; Reperfusion Injury

Cortical spreading depression (CSD) is characterised by slowly propagating waves of cellular depolarization and depression and involves transient changes in blood flow, ion balance and metabolism. In cerebral ischaemia, peri-infarct CSD-like depolarization potentiates infarct growth, whereas preconditioning with a CSD episode protects against subsequent ischaemic insult. Thus, many of the long-lasting molecular changes that occur in CSD-affected tissue are presumed to be part of a 'neuroprotective cascade.' 3',5'-Cyclic guanosine monophosphate (cGMP) has been shown to be a neuroprotective mediator and the nitric oxide system, which increases cGMP production by soluble guanylate cyclase, is up-regulated by CSD. Atrial and C-type natriuretic peptide (ANP/CNP) are present in cerebral cortex and their actions are mediated via particulate guanylate cyclase receptors and cGMP production. Therefore, in further efforts to characterise the role of cGMP-related systems in CSD and neuroprotection, this study investigated possible changes in cortical natriuretic peptide expression following acute, unilateral CSD in rats. Using in situ hybridisation, significant 20-80% increases in ANP mRNA were detected in layers II and VI of ipsilateral cortex at 6 h and 1-14 days after CSD. Ipsilateral cortical levels were again equivalent to control contralateral values after 28 days. Assessment of cortical concentrations of ANP immunoreactivity by radioimmunoassay revealed a significant 57% increase at 7 days after CSD. Despite using a sensitive signal-amplification protocol, authentic ANP-like immunostaining was readily detected in subcortical nerve fibres, but was not reliably detected in normal or CSD-affected neocortex, suggesting the presence of very low levels, and/or active or differential processing of the peptide. Cortical CNP mRNA levels are not altered by CSD, indicating the specificity of the observed effects.Overall, these novel findings demonstrate a prolonged increase in cortical ANP expression after an acute episode of CSD. The overlap between the described time course of CSD-induced protection against ischaemic insult and demonstrated increases in ANP levels, suggest that ANP (like nitric oxide) may contribute to CSD-induced neuroprotection, via effects on cGMP production and other signal-transduction pathways.

Topics: Animals; Atrial Natriuretic Factor; Brain Ischemia; Cell Survival; Cerebral Cortex; Cerebral Infarction; Cortical Spreading Depression; Cyclic GMP; Gene Expression; Ischemic Preconditioning; Male; Neurons; Potassium Chloride; Rats; Rats, Sprague-Dawley; Reaction Time; RNA, Messenger; Signal Transduction; Up-Regulation

N-methyl-D-aspartate receptors (NMDARs) mediate ischemic brain damage but also mediate essential neuronal excitation. To treat stroke without blocking NMDARs, we transduced neurons with peptides that disrupted the interaction of NMDARs with the postsynaptic density protein PSD-95. This procedure dissociated NMDARs from downstream neurotoxic signaling without blocking synaptic activity or calcium influx. The peptides, when applied either before or 1 hour after an insult, protected cultured neurons from excitotoxicity, reduced focal ischemic brain damage in rats, and improved their neurological function. This approach circumvents the negative consequences associated with blocking NMDARs and may constitute a practical stroke therapy.

Topics: Amino Acid Sequence; Animals; Brain; Brain Ischemia; Calcium; Cells, Cultured; Cerebral Infarction; Cyclic GMP; Disks Large Homolog 4 Protein; Guanylate Kinases; In Vitro Techniques; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; N-Methylaspartate; Nerve Tissue Proteins; Neurons; Patch-Clamp Techniques; Peptides; Protein Binding; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, N-Methyl-D-Aspartate; Recombinant Fusion Proteins; Signal Transduction; Synaptic Transmission

The multiple experimental parameters of different aspects in this study were determined in the patients with "Liver Yang Forming Wind Syndrome (LYFWS)", "Qi Deficiency Blood Stagnation Syndrome (QDBSS)" and "Yin Deficiency Forming Wind Syndrome (YDFWS)". The results showed that cerebral hemorrhage was similar to cerebral infarction in almost all parameters and the two diseases were with LYFWS. It was found that there were several characteristics in LYFWS, i.e. 1. Hyperfunction of sympathetic adrenal medullary system. 2. Hypotriiodothyroidoglobulin syndrome. 3. The marked changes of the active substance regulating vessel smooth muscle function. 4. The increased inflammatory medicators. The pathophysiological parameters in patients with QDBSS were the same as those with YDFWS, but the changes of QDBSS and YDFWS weRe milder than those of LYFWS.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Cerebral Hemorrhage; Cerebral Infarction; Cyclic AMP; Cyclic GMP; Diagnosis, Differential; Female; Humans; Male; Medicine, Chinese Traditional; Middle Aged; Norepinephrine; Thromboxane B2

Topics: Animals; Biological Assay; Carotid Stenosis; Cell Line; Cerebral Infarction; Cyclic GMP; Female; Fibroblasts; Humans; Ischemic Attack, Transient; Male; Middle Aged; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Nitric Oxide; Rats

The cerebroprotective effects of mild hypothermia have been extensively studied in various animal models of ischemia, but the mechanism by which mild hypothermia diminishes ischemic injury is not well understood. Nitric oxide (NO) has been implicated as a mediator of glutamate excitotoxicity in primary neuronal cultures, and its synthesis is acutely increased during focal ischemia in vivo. To evaluate possible mechanisms of hypothermic neuroprotection, we measured markers of NO synthesis--nitrite and cyclic guanosine monophosphate (cGMP) levels and NO synthase activity--during right middle cerebral artery occlusion (MCAO) in the rat under normothermic (36.5 degrees C) and mild hypothermic (33 degrees C) conditions. There was a significant increase in nitrite concentration in the right hemisphere versus the left under normothermic conditions at 10 and 20 minutes after MCAO (P < 0.01), with a return to baseline levels by 60 minutes. The increase in cortical nitrite levels in the right hemisphere versus the left was not observed with mild hypothermia. There was a threefold increase in cGMP synthesis in the normothermic right cortex 10 minutes after MCAO (P < 0.05). This rise in cGMP did not occur in hypothermic animals, and the right to left cortical disparity in cGMP production was abolished. Finally, the significant increase in NO synthase activity seen in the normothermic ischemic cortex was absent in hypothermic rats (P < 0.05). These results suggest that mild hypothermia (33 degrees C) modulates the burst of nitric oxide synthesis during cerebral ischemia and may account, at least partially, for its cerebroprotective effects.

Topics: Amino Acid Oxidoreductases; Animals; Brain Damage, Chronic; Cerebral Cortex; Cerebral Infarction; Cyclic GMP; Energy Metabolism; Hypothermia, Induced; Male; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Wistar; Regional Blood Flow

The content of cyclic nucleotides (cAMP and cGMP), hormones (T3, T4, insulin, protein-bound iodine and thyroid-stimulating hormone) and phosphodiesterase activity were examined in the acute period and over time in blood plasma of patients with ischemic stroke. The parameters under study were found to be interrelated. Also, it has been established that the T4/T3 and cAMP/cGMP ratios and the content of insulin may serve as important biochemical criteria for the gravity of ischemic stroke.

Topics: Acute Disease; Brain Ischemia; Cerebral Infarction; Cyclic AMP; Cyclic GMP; Humans; Insulin; Nucleotides, Cyclic; Phosphoric Diester Hydrolases; Thyroxine; Triiodothyronine