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T Kirino

Publications and source records attributed to T Kirino.

At least 19 recordsLinked to original sources
PubMed1992

Abnormal Ca2+ homeostasis before cell death revealed by whole cell recording of ischemic CA1 hippocampal neurons.

Slices were made from the hippocampus of gerbils following transient ischemia achieved by clamping the carotid arteries for 5 min, and changes in the electrophysiology of CA1 pyramidal neurons were studied by whole cell patch-clamp recording as well as conventional intracellular recording. The great majority of CA1 neurons in slices made 2.5-3 days after ischemia showed reduced resting potentials and were easily depolarized by prolonged low-frequency stimulation or by tetanic stimulation of the Schaffer collateral/commissural input. This stimulus-induced depolarization was accelerated by intracellular injection of D-myo-inositol 1,4,5-triphosphate, which depolarized membrane potentials towards 0 mV without synaptic input stimulation. Intracellular application of BAPTA, a Ca2+ chelator, effectively blocked the stimulus-induced depolarization. When recording from ischemic neurons with patch pipettes containing both D-myo-inositol 1,4,5-triphosphate and BAPTA, excitatory postsynaptic currents were transiently potentiated by stimulation, but the membrane potential did not show stimulus-induced depolarization and remained steady for long periods. These results lend support to the view that the intracellular Ca2+ regulation system is severely disturbed following ischemia, and that input fiber stimulation leads to abnormal Ca2+ accumulation in ischemic neurons resulted in neuronal death. The reduction of free Ca2+ inside the ischemic neuron by BAPTA apparently saves neurons which are otherwise destined to delayed neuronal death.

Animals↗
PubMed1992

Disturbance of membrane function preceding ischemic delayed neuronal death in the gerbil hippocampus.

Slice preparations were made from the hippocampus of gerbils after 5 min of ischemia by carotid artery occlusion and the membrane properties of pyramidal neurons were examined. A majority of CA1 neurons lost the capacity for long-term potentiation following tetanic stimulation of the input fibers. CA3 pyramidal neurons, in contrast, preserved responses similar to those in the normal gerbil. Following ischemia, CA1 pyramidal neurons showed increased spontaneous firing that was highly voltage dependent and was blocked by intracellular injection of the Ca2+ chelator, EGTA. Thirty-five percent of CA1 neurons showed an abnormal slow oscillation of the membrane potential after 24 h following ischemia. Intracellular injection of GTP gamma S or IP3 produced facilitation of the oscillations followed by irreversible depolarization. Our results indicate that ischemia-damaged CA1 neurons suffer from abnormal Ca2+ homeostasis, involving IP3-induced liberation of Ca2+ from internal stores.

Animals↗
PubMed1992

Localization of arachidonate 12-lipoxygenase in canine brain tissues.

The cytosol fraction from a thoroughly irrigated canine cerebrum was subjected to immunoaffinity chromatography using a monoclonal antibody against porcine leukocyte 12-lipoxygenase. Arachidonate 12-lipoxygenase eluted from the column with some retardation. The enzyme, with a specific activity of 9 nmol/min/mg of protein, converted arachidonic acid to 12(S)-hydroperoxy-5,8,10,14-eicosatetraenoic acid. The enzyme was active not only with arachidonic acid, but also with linoleic and alpha-linolenic acids. In contrast, 12-lipoxygenase of canine platelets was almost inactive with linoleic and alpha-linolenic acids, and the platelet enzyme was also distinguished from the cerebral enzyme in terms of reactivity with the anti-12-lipoxygenase antibody. 12-Lipoxygenase activity was also detected in the cytosol fractions of other parts of canine brain: basal ganglia, hippocampus, cerebellum, olfactory bulb, and medulla oblongata.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1991

Effects of thyrotropin-releasing hormone on behavioral disturbances in middle cerebral artery-occluded rats.

The effects of thyrotropin releasing hormone (TRH) on behavioral and histological changes were studied in rats subjected to left middle cerebral artery occlusion. The drug was given i.p. once or several times a day from 1 week after occlusion for 2 weeks. A single administration of TRH (1 and 10 mg/kg) did not affect the neurological deficits, but recovery of the deficits was accelerated by multiple administration (7 times a day) of TRH and single administration (once a day) of YM-14673 (N alpha-[[(S)-4-oxo-2-azetidinyl]carbonyl]-L-histidyl-L-prolinamide dihydrate), a new TRH analogue with a longer half-life. Both YM-14673 and single (1 and 10 mg/kg) and multiple administration of TRH ameliorated the disturbance of passive avoidance learning. Neuronal degeneration in the cerebral cortex and striatum was not influenced by the administration of TRH. Thus, we found that neurological deficits and disturbance of passive avoidance learning behavior in middle cerebral artery-occluded rats could be ameliorated by administration of TRH.

Animals↗
PubMed1991

Induced tolerance to ischemia in gerbil hippocampal neurons.

Brief ischemia induced tolerance to subsequent ischemia in the hippocampal neurons. Male Mongolian gerbils were subjected to 2 min of ischemia in an awake condition. This ischemic insult only rarely produced neuronal damage in the gerbil brain. One day (n = 9), 2 days (n = 9), or 4 days (n = 10) following the first brief ischemia, the animals (double-ischemia group) were subjected to the second ischemia for 5 min. The single-ischemia group received a sham procedure instead of the first ischemia and was identically subjected to the second ischemia 1 day (n = 9), 2 days (n = 10), and 4 days (n = 13) following the sham procedure. One week following the second ischemia, all gerbils were perfusion fixed and the neuronal density in the hippocampal CA1 sector was measured. In double-ischemia groups, the neuronal density per 1-mm length of the pyramidal cell layer was 103.4 +/- 93.1 (SD) in the 1-day subgroup, 125.6 +/- 64.2 in the 2-day subgroup, and 176.2 +/- 93.7 in the 4-day subgroup, while the density in normal gerbils was 254.7 +/- 18.6. The average neuronal density in the single-ischemia group was much lower than that in the double-ischemia group (whole control group: 10.9 +/- 27.4). Immunostaining using monoclonal antibody raised against 70-kDa heat-shock protein revealed an increase in 70-kDa heat-shock protein in the CA1 area following 2 min of ischemia. Very brief ischemia induces heat-shock proteins and, presumably, thereby renders neurons more tolerant to subsequent metabolic stress.

Animals↗
PubMed1991

Lithium ion does not protect brain against transient ischemia in gerbils.

It has been proposed that lithium ion desensitizes neuronal receptors that function via the inositol phospholipid signaling mechanism. We examined the effects of lithium chloride on the morphologic outcome after 5 minutes of cerebral ischemia induced in gerbils by occluding both common carotid arteries under brief halothane anesthesia. In three treated groups of 10 gerbils each, 5 meq/kg i.p. lithium chloride was given 2 days, 1 day, and 2 hours before ischemia; 2 hours before ischemia; or immediately after the end of ischemia. Corresponding control groups of nine or 10 gerbils each received equivalent volumes of saline injected at comparable times. All gerbils were perfusion-fixed 1 week later, and neuronal density of the hippocampal CA1 pyramidal cells was determined. Lithium induced very mild intraischemic systemic hypothermia, but postischemic hyperthermia developed in both treated and control groups. Neuronal densities were equal in corresponding groups. The results indicate that our regimen of lithium administration provides no benefit in survival of hippocampal neurons, and intraischemic hypothermia of less than 0.8 degrees C is not protective. Other strategies to inactivate the signal transduction system that is specific for excitatory neurotransmission should be evaluated.

Animals↗
PubMed1991

Thalamic atrophy following cerebral infarction in the territory of the middle cerebral artery.

We investigated shrinkage of the ipsilateral thalamus following infarction in the territory of the middle cerebral artery in 33 patients who were admitted less than or equal to 2 days after the stroke and who were followed by computed tomography for greater than 1 year with no recurrences. The thalamic area was measured on the computed tomograms, and the ratio of the ipsilateral area to the contralateral area was calculated. All values were compared with values from the initial computed tomogram taken less than or equal to 2 days after the stroke. The values of the ratio on follow-up computed tomograms decreased gradually in 15 patients. In these cases, the area of the ipsilateral thalamus was significantly reduced after 1 year (p less than 0.01) and marked atrophy was observed. These results demonstrate the significance of remote changes over a long period of time after focal cerebral infarction.

Atrophy↗
PubMed1990

Suppressive effect of E-64c on ischemic degradation of cerebral proteins following occlusion of the middle cerebral artery in rats.

Microtubule-associated protein 2 (MAP2) levels in the left cerebral hemisphere decreased significantly 3 days after occlusion of the left middle cerebral artery in rats to 29 +/- 16.3% of control levels. Since MAP2 is one of the substrates of calpain, E-64c, a synthetic calpain inhibitor, was administered at a dose of 400 mg/kg twice a day for 3 days, with the first dose being given before the production of ischemia. This depletion was significantly inhibited in vivo by E-64c (P less than 0.05) to increase MAP2 levels to 55 +/- 25.7% of control levels. E-64c had no significant effect on the ischemia-induced depletion of myelin-associated glycoprotein. Sham-operated rats were used as controls. Our results suggest that calpain is partially involved in the degradation of MAP2, and that the use of calpain inhibitors can be a useful clinical approach to cerebral ischemia.

Animals↗
PubMed1990

Chronic maintenance of presynaptic terminals in gliotic hippocampus following ischemia.

Following brief cerebral ischemia, neurons are selectively damaged and die, whereas glial cells and blood vessels survive. This phenomenon of selective vulnerability is well illustrated in the hippocampal CA1 region. Five min of forebrain ischemia in the Mongolian gerbil produced selective neuronal necrosis in the hippocampal CA1 sector. After destruction and loss of CA1 neurons, a remarkable glial reaction (gliosis) was seen. The thickness of the CA1 subfield remained unchanged until 1 month after ischemia and then gradually shrank over several months. Ultrastructural observation of this region revealed persistent maintenance of presynaptic structures. Numerous presynaptic terminals containing synaptic vesicles were scattered throughout the gliotic scar tissue. These presynaptic terminals were apposed to degenerative structures which seemed most likely to be remnants of dendrites. In another group of animals, at one month following ischemic damage in the CA1 sector, the CA3 neurons were destroyed by kainic acid injection. In these animals, numerous degenerating presynaptic boutons were seen in the CA1 sector when fixed 4 days following kainate injection. These results indicate that even in gliotic tissue, presynaptic terminals can survive and maintain their structural characteristics although neuronal cell bodies are almost absent.

Animals↗
PubMed1990

Atrophy of the ipsilateral substantia nigra following middle cerebral artery occlusion in the rat.

Following occlusion of the left middle cerebral artery in the rat, marked atrophy was observed in the ipsilateral substantia nigra in and after the second week. The mechanism of this neuropathological change in the substantia nigra, which is remote from the site of infarction, may be explained by transsynaptic, neurotransmitter-mediated disinhibition as a result of infarction of the striatum.

Animals↗
PubMed1990

Progressive shrinkage of the thalamus following middle cerebral artery occlusion in rats.

Permanent middle cerebral artery occlusion in rats results in infarction in the ipsilateral cortex and caudate nucleus-putamen. In this ischemia model, severe shrinkage of the ipsilateral half of the thalamus was observed several months after surgery. We examined the serial profile of this phenomenon in 40 rats at intervals from 2 weeks to 6 months after the operation. The area of the ipsilateral half of the thalamus as a percentage of the area of the contralateral half was 87% at 2 weeks, 77% at 1 month, 54% at 3 months, and 54% at 6 months. Such severe morphologic change distant from the original ischemic focus has not been reported in models of experimental focal ischemia. Retrograde degeneration is thought to play an important role in this phenomenon.

Animals↗
PubMed1990

Changes in the concentrations of cerebral proteins following occlusion of the middle cerebral artery in rats.

Using an immunoblotting technique, we investigated changes in the concentrations of microtubule-associated protein 2, 200-kDa neurofilament, tubulin, myelin-associated glycoprotein, and 2':3'-cyclic nucleotide 3'-phosphodiesterase in the brains of 40 rats following occlusion of the left middle cerebral artery or sham operation. Compared with those 4 hours after surgery, concentrations of all proteins decreased significantly in the left hemisphere 3 days after surgery (p less than 0.01). Microtubule-associated protein 2 was the most susceptible to ischemia, and its mean +/- SEM concentration decreased to 23 +/- 9.4% of that in concurrent sham-operated controls. Degradation products of microtubule-associated protein 2 and myelin-associated glycoprotein were detected on the blots. Furthermore, in the contralateral hemisphere (where calpain might be activated), concentrations of these two proteins decreased to 57 +/- 12.0% and 83 +/- 4.3% of those in concurrent sham-operated controls, respectively, 3 days after surgery. Changes in the concentrations of cerebral proteins in the contralateral hemisphere are important for understanding clinical symptoms not attributable solely to the ipsilateral lesion following a focal cerebral stroke.

Animals↗
PubMed1990

Ammon's horn sclerosis: its pathogenesis and clinical significance.

Sclerosis of the cornu Ammonis or Ammon's horn sclerosis (AHS) is an "often-described, yet hitherto enigmatic phenomena" as Spielmyer put it in 1927. It has been found in cases with ischemia, anoxia or hypoglycemia and in more than half of the epileptic brains examined at autopsy. Various theories about its pathogenesis have been propounded. Among them, the "Pathoklise" theory of the Vogts and the vascular theory of Spielmeyer and his associates were prevailing until recently. In 1953, two articles were published to contribute to the pathogenesis of ictal automatism (a type of complex partial or temporal lobe seizures). One is the incisural sclerosis theory by Penfield and his associates and the other is the Ammon's horn sclerosis theory by Sano and Malamud. The former authors described a diffuse sclerosis of the infero-mesial temporal structures without, however, specifically relating it to AHS. They considered it was the result of localized anoxia of that portion of the brain caused by incisural herniation occurring during parturition. Sano and Malamud maintained that AHS is a result of convulsions, a distinct scar adjacent to which epileptogenic foci may develop in the course of time to cause ictal automatism. The latter theory was corroborated by Sano, Falconer and others. Falconer expanded the theory to the assertion that not only ictal automatism but other types of intractable epilepsy may be due to "mesial temporal (Ammon's horn) sclerosis". The most recent development in the pathogenesis of AHS is the excitotoxicity theory. Namely, AHS is caused by excessive excitation of neurons, probably by putative excitatory neurotransmitters, especially, glutamate. For this theory, there is a significant body of evidence. The problem of AHS, an old research subject and a matter of long-lasting controversy, has now been updated and become one of the newest topics in the field of experimental neurobiology.

Animals↗
PubMed1989

Allopurinol inhibits uric acid accumulation in the rat brain following focal cerebral ischemia.

Uric acid (UA) in the rat brain was measured by HPLC with an electrochemical detector following focal ischemia. At 24 h after the operation, the UA level in the ischemic center was 105.47 +/- 8.39 nmol/g tissue, whereas it was 8.36 +/- 1.86 in the sham-operated group. Allopurinol, xanthine oxidase inhibitor, almost completely inhibited this UA accumulation. These data demonstrate that the UA increase in the ischemic brain is due to the xanthine oxidase reaction.

Allopurinol↗
PubMed1989

Effects of a new thyrotropin-releasing hormone derivative on behavioral changes after focal cerebral ischemia in rats.

We observed the effects of a new thyrotropin-releasing hormone derivative, YM-14673 (N alpha-[[(S)-4-oxo-2-azetidinyl]carbonyl]-L-histidyl-L-prolinamide dihydrate), on behavioral changes in rats for 3 weeks after focal cerebral ischemia. Under halothane anesthesia, the left middle cerebral artery was occluded via a transretro-orbital approach. YM-14673 was administered just after the operation and once a day for 3 weeks. Neurologic deficits, including hemiplegia and abnormal posture, and disturbance of passive avoidance learning were present in solvent-treated control rats for the entire 3 weeks. YM-14673 at 0.1 or 0.3 mg/kg i.p. or 1 mg/kg p.o. significantly accelerated the recovery of neurologic deficits and ameliorated cognitive disturbance compared with the solvent-treated controls although the drug at 0.1 and 0.3 mg/kg i.p. did not influence the size of the ischemic infarct. YM-14673 mitigated the behavioral disturbances in this model of chronic focal cerebral ischemia. We also discuss the suitability of this model for the evaluation of drugs.

Animals↗
PubMed1989

Effect of cyclooxygenase and lipoxygenase inhibitors on delayed neuronal death in the gerbil hippocampus.

The purpose of our study was to examine whether cyclooxygenase and lipoxygenase inhibitors ameliorate delayed neuronal death in the hippocampal CA1 sector in Mongolian gerbils after 5 minutes of forebrain ischemia. Gerbils were injected intraperitoneally with cyclooxygenase inhibitors piroxicam and flurbiprofen or with lipoxygenase inhibitors AA-861 and BW-755C. Seven days after ischemic insult, the animals were perfusion-fixed, and the neuronal density in the hippocampal CA1 sector was estimated. The average neuronal density in unoperated normal gerbils was 247 +/- 9/mm (mean +/- SEM). In ischemic gerbils with vehicle administration, the average neuronal densities were 13 +/- 2, 14 +/- 2, 13 +/- 2, and 13 +/- 1 for piroxicam, flurbiprofen, AA-861, and BW-755C, respectively. The average neuronal densities in ischemic gerbils treated with 1.5 and 10 mg/kg piroxicam and 1.5 and 10 mg/kg flurbiprofen were 13 +/- 2, 194 +/- 9, 19 +/- 5, and 143 +/- 12, respectively. In ischemic gerbils treated with 15 and 100 mg/kg AA-861 and 30 mg/kg BW-755C, the average neuronal densities were 12 +/- 1, 13 +/- 1, and 14 +/- 2, respectively. At their higher doses, both piroxicam and flurbiprofen significantly (p less than 0.01) ameliorated delayed neuronal death in the hippocampal CA1 sector. Our results suggest that cyclooxygenase products play an important role in the development of delayed neuronal injury after cerebral ischemia.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1989

Effects of a new thyrotropin-releasing hormone analogue administered in rats 1 week after middle cerebral artery occlusion.

We observed the effects of a new thyrotropin-releasing hormone analogue, YM-14673 (N alpha-[[(S)-4-oxo-2-azetidinyl]carbonyl]-L-histidyl-L-prolinamide dihydrate) on behavioral changes in 26 rats subjected to middle cerebral artery occlusion. The administration of 0.1 mg/kg i.p. YM-14673 was started 1 week after occlusion and was repeated daily for 2 weeks. YM-14673 significantly accelerated the recovery of neurologic deficits and ameliorated the disturbance of passive avoidance learning. Thus, YM-14673 improved behavioral response in a model of chronic focal cerebral ischemia. The availability of a chronic middle cerebral artery occlusion model for the evaluation of drugs is also discussed.

Animals↗