Masami Eigyo

Central effect of atrial natriuretic polypeptide on angiotensin II-stimulated vasopressin secretion in concious rats

The effect of intracerebroventricular (i.c.v.) treatment of alpha-human atrial natriuretic polypeptide on the vasopressin secretion induced by i.c.v. injection of angiotensin II was studied in conscious, unrestrained rats. Pretreatment of alpha-human atrial natriuretic polypeptide (5 micrograms) significantly inhibited the angiotensin II (100 ng)-stimulated vasopressin secretion. This result suggests that atrial natriuretic polypeptide plays regulatory roles in vasopressin secretion in the central nervous system.

Central action of atrial natriuretic polypeptide on blood pressure in conscious rats

The effect of intracerebroventricular administration of atrial natriuretic polypeptide on blood pressure was studied in conscious, unrestrained rats. The intracerebroventricular injection of alpha-human atrial natriuretic polypeptide did not promote any significant change in basal blood pressure, whereas it attenuated central angiotensin II-induced pressor response in a dose-dependent manner. The plasma atrial natriuretic polypeptide level did not change after the central administration of alpha-human atrial natriuretic polypeptide. These data implicate atrial natriuretic polypeptide as a factor in blood pressure regulation in the central nervous system.

Ischemia-induced irreversible deficit of memory function in gerbils

Ischemia for 5 min temporarily increased locomotor activity in gerbils after 1 and 3 days. Temporary increases were also noted within 7 and 5 days after 20-min ischemia and repeated ischemia (three 2-min ischemia at 1-h intervals), respectively. In a passive avoidance task, gerbils were trained 2 or 14 days before the occlusion and then tested 1 day after it. Shortened step-through latency was observed in the retention test 3 days after 5-min ischemia, but not after 15 days (reversible deficit). In contrast, following 20-min ischemia, the step-through latency was significantly lower after 3 days and also after 15 days (irreversible deficit). Working memory was also tested with gerbils trained for an 8-arm radial maze task. A significantly higher working error was observed 1 day after 5-min ischemia but not after 5 days (reversible deficit). However, ischemia for 20-min and repeated ischemia led to markedly increase working error 1 day after the occlusion, with significant increases even after 14 and 28 days (irreversible deficit). In addition, while 5-min ischemia occurred the neuronal death in the hippocampal CA1 subfield, 20-min ischemia produced it not only in the CA1 subfield but also in the CA2-4 subfield and dorsal striatum. These results indicated that 5-min ischemia led to a reversible memory deficit, while 20-min and repeated ischemia produced an irreversible deficit.

Possible involvement of central atrial natriuretic polypeptide in regulation of hypothalamo-pituitary-adrenal axis in conscious rats

The effects of intracerebroventricular (i.c.v.) administration of angiotensin II (AII) and atrial natriuretic polypeptide (ANP) on the plasma corticosterone level were studied in conscious, unrestrained rats. Although i.c.v. injection of ANP had no apparent effect on the basal plasma corticosterone level, it attenuated the plasma corticosterone increase induced by centrally injected AII dose-dependently. These results suggest that ANP in the brain is involved in the regulation of the hypothalamo-pituitary-adrenal axis.

Protective effect of CCK-8 and ceruletide on glutamate-induced neuronal cell death in rat neuron cultures: possible involvement of CCK-B receptors.

Cholecystokinin octapeptide (CCK-8), ceruletide (CLT) and gastrin-I, which were added simultaneously with glutamate to rat neuron cultures, significantly suppressed the neuronal cell death induced by glutamate which can be observed from the efflux of lactate dehydroxylase into the culture medium. However, gastrin-I (1-13) had no effect on the response to glutamate. The inhibitory effect of CLT on glutamate-induced neuronal cell death could be completely blocked by a selective antagonist for CCK-B receptors, (+)L-365,260. These findings clearly indicate that CCK-8, CLT and gastrin-I exhibit a protective effect against glutamate-induced neurotoxicity via the CCK-B receptor.

A novel benzodiazepine inverse agonist, S-8510, as a cognitive enhancer

1. Pharmacological actions of a novel benzodiazepine receptor ligand, S-8510 (2-(3-isoxazolyl)-3,6,7,9-tetrahydroimidazo[4,5-d]pyrano+ ++[4,3-b] pyridine monophosphate monohydrate), were examined in in vitro and in vivo studies. 2. S-8510 was characterized as a partial inverse agonist with a modest GABA ratio and low efficacy. 3. S-8510 ameliorated memory impairment induced by cholinergic deficit in the water maze paradigm of Wistar rats. 4. S-8510 augmented LTP of the Schaffer collateral/commissural fiber-CA1 synapses in the hippocampal slice preparations of SD rat. 5. S-8510 increased the extracellular levels of acetylcholine and noradrenaline in the hippocampus of Wistar rat. 6. S-8510 selectively potentiated pentylenetetrazol-induced convulsion without affecting minimal electroconvulsive shock- or strychnine-induced convulsion in ddY mice. 7. S-8510 failed to induce any sign of anxiety in the Wistar rat pro-conflict test. 8. S-8510 showed antidepressant-like pharmacological actions in ddY mice. 9. These results suggest that S-8510 can be used as a therapeutic drug for senile dementia, including Alzheimers disease with little risk for inducing anxiety or convulsion.

Differential effects of sulpiride and metoclopramide on brain

SummarySulpiride (SUL) is more efficacious in antipsychotic activity than metoclopramide (MET), although both appear to possess almost equal affinities for dopamine (DA) receptors. We studied the effects of SUL and MET on the brain homovanillic acid (HVA) level and shuttle box avoidance to clarify their differential modes of action on the blockade of DA receptors. SUL was several times less potent than MET, which was about 50 times less potent than the control drug haloperidol (HAL), for increasing HVA at 4 h after s.c. administration. However, SUL was about 50 times more potent than MET and about equipotent to HAL, at 2 h after drug administration into the lateral ventricle. The potency of SUL by intraventricular administration was 20-fold or more than that by intracisternal administration. HAL and MET did not show such a discrepancy. The HVA level reached the maximum 1 h after intraventricular administration of MET or HAL, while s.c., intracisternal or intraventricular administration of SUL caused a gradual increase in the HVA level with the maximum being reached after 6–8 h. In shuttle box avoidance, MET was about 25 times more potent than SUL by intraperitoneal administration but about 200 times less potent than SUL, which was about 10 times more potent than HAL, by intraventricular administration. These results suggest that SUL causes a potent, long-lasting blockade of DA receptors, while MET has only a weak, short-lasting action. These findings may be related to the differences in their clinical efficacy.

Systemic administration of a cholecystokinin analogue, ceruletide, protects against ischemia-induced neurodegeneration in gerbils

The neuroprotective action of a cholecystokinin octapeptide analogue, ceruletide, was evaluated in models of cerebral ischemia using Mongolian gerbils. Ceruletide significantly suppressed the hyperactivity and amnesia induced by ischemia when injected s.c. 30 min before 5-min occlusion of the bilateral common carotid arteries at room temperature or immediately after their reperfusion. Ceruletide also reduced behavioral changes in ischemic gerbils whose body temperature was maintained at 37 degrees C during the 3-min occlusion. In these groups, delayed neuronal cell death in the hippocampal CA1 area following ischemia was markedly attenuated by s.c. administration of ceruletide. On the other hand, ceruletide could not inhibit the behavioral changes or the neurodegeneration induced in the hippocampal CA1 area by 5-min occlusion at 37 degrees C. These findings indicate that peripheral injection of ceruletide produces a neuroprotective action against moderate cerebral ischemia, which is the first evidence suggesting the efficacy of ceruletide in neurodegenerative diseases.

Inhibitory effect of CCK-8 and ceruletide on glutamate-induced rises in intracellular free calcium concentrations in rat neuron cultures

To study the mechanism by which cholecystokinin octapeptide (CCK-8) and its potent analogue, ceruletide, prevent glutamate-induced neuronal cell death in rat neuron cultures, we examined the effect of both peptides on glutamate-induced increases in the intracellular free calcium concentrations ([Ca2+]i), which are known to be a crucial trigger of the neurodegeneration induced by glutamate. CCK-8 itself did not alter [Ca2+]i in rat neuron cultures. Glutamate increased [Ca2+]i in neuron cultures rapidly and markedly. CCK-8 and ceruletide significantly suppressed the increases in [Ca2+]i induced by glutamate. The maximum inhibitory effects of CCK-8 and ceruletide at 10(-6) M reached 43 and 46% of the response to glutamate, respectively. Gastrin-I and CCK-4 also significantly attenuated the increases in [Ca2+]i induced by glutamate. The inhibitory effect of CCK-8 was completely blocked by the selective antagonist for CCK-B receptors, (+)L-365,260, but not by (-)L-364,718, which is a selective antagonist for CCK-A receptors. CCK-8 significantly suppressed [Ca2+]i response to kainate and high concentrations of extracellular K+, but not to N-methyl-D-aspartate. With cultured astrocytes, CCK-8 did not inhibit the increment of [Ca2+]i induced by glutamate. These findings clearly demonstrated that CCK-8 and ceruletide inhibit glutamate-induced increases in [Ca2+]i in neuron cultures through CCK-B receptors, suggesting that CCK-8 may participate in the central actions of glutamate.

Activation of brain function by S-135, a benzodiazepine receptor inverse agonist

1. S-135, 2-(5-methylthien-3-yl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinoline-3- one, bind binds to benzodiazepine receptors with a high affinity and shows pharmacological actions opposite to those of conventional benzodiazepine drugs. 2. S-135 induced no convulsion in mice by itself, but selectively potentiated the effect of subconvulsive dose of pentylenetetrazole. 3. S-135 potentiated rat crossed extensor reflex and Ro 15-1788 completely antagonized this potentiation. 4. S-135 antagonized pentobarbital-induced anesthesia, tetrabenazine-induced ptosis and reserpine-induced hypoactivity and shortened immobilization time in the despair test in mice, indicating that this compound possesses antidepressive properties. 5. S-135 antagonized amnesia in mice and rats in passive avoidance tasks. 6. Glucose utilization in brain areas relating to memory and arousal functions was enhanced following S-135 treatment. 7. These results indicate that S-135 can be a useful drug for activating depressed brain function.