Shun-ichi Yamaguchi

Hypoxic-ischemic cerebral necrosis in midgestational sheep fetuses: Physiopathologic correlations

Thirty-eight midgestational sheep fetuses were exposed 120 min to marked hypoxia. The brains in eight that reduced their mean arterial blood pressure to less than 30 mm Hg were markedly damaged. In these same fetuses the serum lactic acid concentrations were elevated during exposure to hypoxia to excessively high values (greater than 15 mM) and remained elevated for a prolonged period during recovery. Twenty-one fetuses exposed to the same magnitude of hypoxia that maintained their blood pressure unchanged showed less marked elevations of serum lactate concentrations and remained brain-intact. Greater quantities of pentobarbital administered to the ewes during hypoxia seemed to protect the brain from hypoxia and this effect was dose-dependent. Exposure of midgestational sheep fetuses to marked hypoxia associated with reductions in cerebral blood flow due to decreased blood pressure and impaired cerebral autoregulation caused major focal cerebral necrosis.

Brain Metabolic Correlates of Hypoxic-Ischemic Cerebral Necrosis in Mid-Gestational Sheep Fetuses: Significance of Hypotension

Midgestational sheep fetuses exposed to marked hypoxia for 2 h remain brain intact if MABP is maintained above 30 mm Hg. On the other hand, similarly hypoxic fetuses, if they experience reductions in MABP below 30 mm Hg, develop foci of necrosis that predominantly affect hemispheric white matter and neostriatum. Cortex damage is more restricted and is usually associated with more massive underlying white matter damage. The present study examines the brain metabolic basis for the important role of hypotension in brain injury development in marked hypoxia. Sheep fetuses rendered hypoxic by respiring their ewes with 11% oxygen (fetal Pao2 = 8–12 mm Hg) in which MABP was maintained above 30 mm Hg showed increases in brain lactic acid concentrations to 7–13 μmol/g but unaltered energy charge. In contrast, fetuses that sustained MABP reductions below 30 mm Hg showed increases in lactic acid concentrations in vulnerable structures to 16–24 μmol/g accompanied by marked decreases in energy charge. The vulnerable structures also showed reductions in fructose concentrations but a variable behavior of other brain metabolites including phosphocreatine, glycogen, and glucose. Thus, the present findings suggest a relation between hypotension during marked hypoxia, low energy charge, lactic acid accumulation in brain at high concentrations, and fetal brain injury. The ewes of hypoxic hypotensive fetuses received pentobarbital at lower doses than did those of fetuses that maintained blood pressure. This suggests that pentobarbital plays an important role in protecting the fetal brain from asphyxia by extending the hypoxic fetuss ability to maintain blood pressure in addition to reducing its brain metabolism.

Brain injury from marked hypoxia in cats: role of hypotension and hyperglycemia.

The present study identifies several factors that govern brain pathologic response to marked hypoxia. None of 13 cats exposed to 25 minutes of marked hypoxia (FiO2 = 3.4%; PaO2 = 17 +/- 3 mm Hg, S.D.) that maintained mean arterial blood pressure (MABP) greater than 65 mm Hg were brain injured after reoxygenation and long term survival. In contrast, 12 of 13 exposed to the same hypoxia but that experienced reductions in MABP less than 45 mm Hg for 4 +/- 1 minutes developed a pattern of brain injury closely resembling that of humans surviving in a persistent vegetative state after cardiorespiratory arrest. Higher serum glucose and lactate concentrations and lower blood pH values significantly correlated with development of hypotension during hypoxia. Four of 8 cats exposed to 21 minutes of marked hypoxia followed by 4 minutes of 100% N2 breathing that also led to hypotension similarly developed brain injury. Among the hypoxic/hypotensive cats the magnitude of the hyperglycemic response to hypoxia as modulated by 0, 1, or 2 days of preexposure fasting, strongly correlated with occurrence and extent of brain damage. Peak cisterna magna CSF lactate concentrations 10 to 30 minutes into recovery distinguished those animals that remained brain-intact (less than 13 mM) from those that developed brain damage (greater than 15 mM) with 100% accuracy. Seven cats developed delayed cardiogenic shock 3 to 12 hours into the recovery period. This outcome was predicted by blood pH values less than 6.70 shortly after resuscitation while all 27 surviving cats exhibited values greater than 6.80.

Anticonvulsant Efficacy of ADCI (5-Aminocarbonyl-10, 11-dihydro-5H-dibenzo[a, d] cyclohepten-5,10-imine) After Acute and Chronic Dosing in Mice

Summary: ADCI (5‐aminocarbonyl‐10, 11‐dihydro‐5H‐dibenzo[a, d] cyclohepten‐5,10‐imine), a low‐affinity uncompetitive N‐methyl‐d‐aspartate (NMDA) antagonist, is a broad‐spectrum anticonvulsant with a favorable side‐effect profile. In the present study, we sought to determine if tolerance develops to the anticonvulsant activity of ADCI, using the maximal electroshock (MES) test to assess seizure protection. Mice were treated with three daily injections of a 2 × ED50, dose for MES protection (18 mg/kg, intraperitoneally, i.p.) or vehicle for 7 or 14 days. On the day after the chronic treatment protocol, all animals received a challenge dose of ADCI (18 mg/kg) and 15 min later were evaluated in the MES test. In control animals, 83–94% of animals were protected and the ADCI plasma levels immediately after the MES test were 5.5–9.7 μg/ml. In treated animals, 29 and 0% of animals were protected at 7 and 14 days, respectively, and the ADCI plasma levels were 77 and 52% of the control values. [3H]Dizocilpine binding to brain NMDA receptors was unaltered by the chronic drug treatment. In subsequent experiments, we determined that 14‐day chronically treated animals could be completely protected by increased doses of ADCI (ED50, 28.9 mg/kg). In both native and chronically treated animals receiving a challenge dose of ADCI, plasma drug levels decreased in two phases, the first with a time constant of ∼55 min and the second with a much slower rate. The estimated plasma concentrations of ADCI reflecting threshold (3–5 pg/ml) and 50% protection (5–7.5 μg/mg) were similar in naive and chronic animals. We conclude that tolerance to ADCI is due to pharmacokinetic factors (enhanced first‐pass metabolism) and does not result from a reduction in anticonvulsant efficacy.

Anticonvulsant 1-Phenylcycloalkylamines: Two Analogues with Low Motor Toxicity When Orally Administered

Summary: 1‐Phenylcyclohexylamine (PCA) and its analogues 1‐phenylcyclopentylamine (PPA) and 1‐(3‐fluoropheny1)cyclohexylamine (3‐F‐PCA) are potent anticonvulsants in the mouse maximal electroshock (MES) seizure test. Unlike the structurally related dissociative anesthetic phencyclidine (PCP), however, which produces motor toxicity at anticonvulsant doses, PCA, PPA, and 3‐F‐PCA protect against MES seizures at 2.2‐ to 3.5‐fold lower doses than those that cause motor toxicity when administered intraperitoneally (i.p.). In the present study, we evaluated the oral anticonvulsant activity of PCA, PPA, and 3‐F‐PCA in mice; we also examined 3‐F‐PCA in rats. All the compounds were orally active in the mouse MES seizure test (ED50 values 14.5, 53.4, and 26.7 mg/kg, respectively). Moreover, 3‐F‐PCA was especially potent in rats, either when administered i.p. (ED50 0.4 mg/kg vs. 9.4 mg/kg in mice) or orally (ED50 0.8 mg/kg). Surprisingly, however, oral PPA failed to cause motor toxicity in mice even at doses that were many times higher than those that were protective in the MES test (TD50 >300 mg/kg). In rats, 3‐F‐PCA also showed a strikingly low oral toxicity (TD50 >50 mg/kg) in relation to its potency as an anticonvulsant. Like PCP, PCA analogues block N‐methyl‐D‐aspartate (NMDA)‐induced behavioral effects and lethality in mice. Moreover, in vitro studies indicate that the compounds act as uncompetitive antagonists of the NMDA receptor‐channel complex. Therefore, their anticonvulsant activity may, at least in part, relate to an interaction with NMDA receptors.

Failure to produce germinal matrix or intraventricular hemorrhage by hypoxia, hypo-, or hypervolemia

Our study with midgestational sheep fetuses failed to support a cause-and-effect relation between marked hypoxia with or without hypo- or hypervolemia and rapid surges of blood pressure and the development of germinal matrix or intraventricular hemorrhage. Twenty-nine percent of fetuses exposed to marked hypoxia concomitantly with manipulations of their blood volume and blood pressure developed widespread cerebral necrosis. However, despite this marked anoxic-ischemic brain injury, none developed any germinal matrix or intraventricular hemorrhage. Rapidly and markedly elevating the blood pressure in these fetuses despite the presumed presence of an impaired autoregulation and a probable elevation of their central venous pressure also failed to cause germinal matrix or intraventricular hemorrhage. Marked hypoxia accompanied by reductions in blood pressure brought about by blood withdrawal produced an 80% delayed fetal mortality but not a single instance of germinal matrix or intraventricular hemorrhage.

Prefrontal lobe functions and the neocortical commissures in monkeys

SummaryMonkeys with the neocortical commissures and the optic chiasm sectioned still exhibit a substantial contralateral generalization of delayed response and delayed alternation learning even though the sensory and motor activities during learning are restricted to a single hemisphere. The commissure and chiasma transections, on the other hand, interrupt the contralateral generalization of unilaterally acquired, visual stimulus (color) dependent Go, No-go performances. The differences in outcome between these two types of tasks appears to depend upon the presence or absence of a cueing of correct performance by specific exteroceptive sensory stimuli.