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Notes: Abstract: When hippocampal cultures were deprived of glucose, massive release of lactate dehydrogenase (LDH), an indicator of neuronal death, occurred via NMDA receptor activation. Addition of pyridoxal phosphate (PLP; 1 and 10 µM) inhibited this LDH release in a concentration-dependent manner. Prior exposure to PLP evoked more potent inhibitory effects on LDH release compared with those treated at the onset of glucose deprivation. Furthermore, PLP inhibited the reduction of intracellular content of pyruvate induced by glucose deprivation, which was accompanied by the reversal of intracellular ATP depletion. A noteworthy elevation of extracellular glutamate in response to glucose deprivation was completely reversed by addition of PLP. Aminooxyacetic acid, a potent inhibitor of PLP-dependent enzymes, antagonized the effects of PLP on LDH release, pyruvate production, and ATP formation. These results suggest that PLP protects neurons from glucose deprivation-induced damage by enhancing the formation of energy-yielding products and relieving extracellular load of glutamate. The observed phenomena further indicate that PLP might be used prophylactically against neuronal death induced by metabolic disorders.

Notes: Abstract: It has been previously reported that Alzheimer's amyloid β protein (Aβ) induces reactive astrocytosis in culture. In the present study, we found that Aβ potently inhibits cellular redox activity of cultured astrocytes, as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction assay. The following comparative studies revealed several differences between these two actions of Aβ on astrocytes. First, Aβ-induced reactive morphological change was suppressed by the presence of serum or thrombin, and Aβ inhibition of cellular redox activity was observed in either the presence or the absence of serum. Second, micromolar concentrations (10 µM or more) were required for Aβ to induce reactive astrocytosis, whereas nanomolar concentrations (0.1–100 nM) were sufficient to inhibit cellular redox activity. Third, the effect of micromolar Aβ was virtually irreversible, but nanomolar Aβ-induced inhibition of cellular redox activity was reversed by washing out Aβ. Furthermore, as it has been reported that Aβ neurotoxicity is mediated by reactive oxygen species, we also examined if similar mechanisms are involved in astrocytic response to Aβ. However, neither Aβ-induced morphological change nor inhibition of redox activity was blocked by antioxidants, suggesting that these effects are not caused by oxidative stress.

Notes: 1. The possible interactions between the renal effects of atrial natriuretic peptide (ANP) and angiotensin II (All) were studied in normal sodium-replete human subjects. Recent investigations have suggested that ANP inhibits the pressor and volume-retaining effects of activation of the renin-angiotensin system. Thus, ANP may attenuate the effects of All on renal haemodynamics or tubular transport.2. ANP (0.1 μg/kg per min, 60 min) was intravenously infused into eight normal human subjects with and without pretreatment with enalapril (20 mg, per oral), an inhibitor of the converting enzyme, and during infusion of All (10 mg/kg per min).3. ANP infusion alone caused increases in the urine volume (from 96 ± 23 to 229 ± 44 mL/h, P 〈 0.05) and urinary sodium excretion (from 11.5 ± 1.6 to 20.9 ± 4.2 mEq/h, P 〈 0.05). These changes were accompanied by an increase in the glomerular filtration rate (from 127 ± 9 to 158 ± 9 mL/min, P 〈 0.05). ANP infusion after enalapril administration lowered the mean blood pressure (from 76 ± 2 to 71 ± 3 mmHg, P 〈 0.05) to a level similar to that observed during ANP infusion alone (from 84 ± 2 to 74 ± 2 mmHg, P 〈 0.01), but did not result in a significant diuresis (from 139 ± 23 to 174 ± 51 mL/h) or natriuresis (from 19.7 ± 2.5 to 14.3 ± 3.4 mEq/h, P 〈 0.05). This combined treatment with a converting enzyme inhibitor and ANP reduced both the glomerular filtration rate (160 ± 9 to 141 ± 10 mL/min) and the renal plasma flow (from 775 ± 49 to 570 ± 45 mL/min, P 〈 0.01).4. The antinatriuretic effects of exogenous All were reversed by superimposed ANP infusion (urinary sodium excretion: from 4.8 ± 1.0 to 24.3 ± 5.2 mEq/h, P 〈 0.01). Under these conditions, the glomerular filtration rate increased (from 114 ± 6 to 156 ± 7 mL/min, P 〈 0.05) to levels similar to those observed with ANP infusion alone. In addition the increased tubular sodium reabsorption induced by All was inhibited by concomitant ANP infusion (fractional proximal tubular sodium reabsorption: from 90.7 ± 3.5 to 80.3 ± 16.6%, P 〈 0.05, fractional post-proximal tubular sodium reabsorption: from 91.5 ± 9.8 to 87.6 ± 8.8%, P 〈 0.05).5. These results suggest that ANP interacts with endogenous All particularly in the glomerulus, to cause a diuresis and natriuresis, and also suggest that ANP inhibits All-induced tubular sodium reabsorption.

Notes: 1. The effects of chronic oral administration of inhibitors of angiotensin converting enzyme (ACE) on the vascular renin–angiotensin system were studied.2. Male Sprague-Dawley rats were treated orally with five ACE inhibitors, captopril, enalapril, ramipril, cilazapril and CS-622 (10 mg/kg per day), for periods of 1–2 weeks. Their mesenteric arteries were then isolated and perfused in vitro with Krebs'-Ringer solution, and the angiotensin II (AII) released into the perfusate was measured under unstimulated and isoproterenol-stimulated conditions. The vascular renin activity was also determined after treatments with ACE inhibitors.3. Treatment with captopril for 1 week suppressed the isoproterenol-stimulated increase in All release, but had little effect on the baseline release. Oral treatment with captopril for 2 weeks or with other ACE inhibitors for 1 week markedly inhibited both the unstimulated and stimulated release of AII from the mesenteric vasculature.4. Both the vascular renin activity and the plasma renin activity increased on captopril treatment, but their changes with time were different.5. These results indicate that virtually complete inhibition of the vascular renin–angiotensin system can be achieved after prolonged treatment with ACE inhibitors, and suggest that the chronic antihypertensive action of ACE inhibitors is not solely due to inhibition of the plasma renin–angiotensin system.

Notes: Recent behavioural studies have provided evidence that the amygdala modulates hippocampal-dependent memory. To test the possibility that the amygdala modulates hippocampal synaptic plasticity, we investigated the effects of surgical lesions of the amygdaloid nuclei on the induction of long-term potentiation (LTP) in the dentate gyrus of anaesthetized rats. Previously we reported that LTP in the dentate gyrus was attenuated by lesion of the basolateral amygdala, but was not affected by lesion of the central amygdala. In the present study, dentate gyrus LTP was significantly attenuated by basomedial amygdala lesion but not by medial amygdala lesion. These results suggest that, among the amygdaloid nuclei, the basomedial and basolateral nuclei are involved in the modulation of hippocampal plasticity. The roles of the basomedial and basolateral amygdala were further supported by experiments examining the effects of electrical stimulation of these nuclei. High-frequency stimulation of the basomedial amygdala alone did not induce dentate gyrus LTP, but when applied at the same time as tetanic stimulation of the perforant path increased the magnitude of the dentate gyrus LTP. Similarly, high-frequency stimulation of the basolateral amygdala enhanced LTP induced by tetanic stimulation of the perforant path. Furthermore, facilitation of dentate gyrus LTP by basomedial or basolateral amygdala stimulation was observed even in rats lesioned in either amygdala, suggesting that neurons in the basomedial and basolateral amygdala can modulate dentate gyrus LTP independently. Activity-dependent facilitation of hippocampal plasticity by the basomedial and basolateral amygdala may underlie memory processing associated with emotion.

Notes: 1. The effects of chronically administered aged garlic extract (AGE) on the age-related changes in a novel strain of senescence accelerated mouse (SAM) characterized by age-related brain atrophy (SAMP10) were investigated.2. A solid diet containing 2% (w/w) AGE was given to SAM from 2 months of age.3. The grading score of senescence in SAMP10 at 10 months of age was significantly higher than that of SAMR1, a reference strain for SAMP10.4. Administration of AGE prevented the increase in the grading score of SAMP10 and SAMR1.5. In behavioural evaluation, AGE improved learning and memory deficits of SAMP10 in both the passive and conditioned avoidance tests as well as the spatial memory test.6. Treatment with AGE in SAMP10 prevented the decrease in brain weight and the atrophic changes in frontal brain at 12 months of age.7. These results raise the possibility that AGE prevents physiological ageing and may be beneficial for age-related cognitive disorders in humans.

Notes: The effect of serotonin 5-HT2 receptor stimulation on long-term potentiation (LTP) in the primary visual cortex was investigated by using rat brain slices in vitro. Field potentials evoked by stimulation of layer IV were recorded in layer II/III. The 5-HT2 receptor agonist 1-(2,5-dimethyl-4-iodophenyl)-2-aminopropane (DOI) did not affect baseline synaptic potentials evoked by single-pulse test stimulation, but significantly inhibited the induction of LTP in a concentration-dependent manner (0.1–10 μm). The LTP-inhibiting effect of DOI (10 μm) was blocked by the 5-HT2,7 receptor antagonist ritanserin (10 μm), but not by the 5-HT1A receptor antagonist NAN-190 (10 μm) nor by the 5-HT3,4 receptor antagonist MDL72222 (10 μm). The inhibitory effect of DOI was also blocked by the phospholipase C inhibitor U73122, but not by its inactive analogue U73343. These results suggest that visual cortex LTP is inhibited by activation of the 5-HT2 receptor–phospholipase C system. In addition, the LTP-inhibiting effect of DOI was abolished by the presence of the GABAA receptor antagonist bicuculline (10 μm), suggesting that 5-HT2 receptor-mediated inhibition of visual cortex LTP is dependent on GABAergic inhibition.

Notes: Disordered immune responses are supposed to alter the function of the central nervous system through the neuroendocrine immunomodulation network. In this paper, we studied the influence of the immune function on learning performances from the angle of pharmacology using aged garlic extract (AGE), an immunomodulator. Splenocyte proliferation, induced by concanavalin A or lipopolysaccharide, and the antibody production response were declined in senescence accelerated mouse-prone 8 (SAMP8) aged 12 months compared with age-matched SAMR1 (SAM-resistant 1). Chronic oral administration of AGE-containing food (2%, w/w) significantly enhanced the immune responses of both SAMP8 and SAMR1. Male ddY mice were thymectomized 4 weeks after birth and fed AGE-containing food after the operation until the experiments were finished. Learning performances, brain monoamine content and choline acetyltransferase (ChAT) activity, as well as the immune response were evaluated 10 months after the operation. Thymectomy resulted in not only immunodeficiency, but also deteriorated learning ability. AGE treatment prevented the reduction of the antibody production response induced by thymectomy and improved the thymectomy-induced deterioration of learning behaviours in passive avoidance performance and in a spatial memory task. The contents of hypothalamic noradrenaline, 3,4-dihydroxyphenylacetic acid and homovanillic acid, and the hypothalamic ChAT activity were increased in thymectomized mice compared to those of sham-operated control, while AGE treatment restored them to the control levels. These results suggest that the improvement of immune function is closely related to the amelioration of age-associated deterioration of learning and memory.

Notes: The supramammillary nucleus (SUM) of the hypothalamus sends neural projections to the hippocampus and is supposed to be involved in learning and memory. To test the possibility that SUM afferents modulate hippocampal functions, we investigated the effect of electrical stimulation of the SUM on the induction of long-term potentiation (LTP) at medial perforant path (PP)–granule cell synapses in the dentate gyrus (DG) of anaesthetized rats. High-frequency stimulation of the SUM (100 pulses at 100 Hz) alone did not change PP–DG field potentials. However, when the SUM stimulation was applied simultaneously with weak tetanic stimulation of the PP (20 pulses at 20 Hz) which alone did not induce any potentiation, it produced a long-lasting potentiation of the population spike, without an accompanying increase in the population excitatory postsynaptic potential (EPSP). The EPSP-spike (E-S) potentiation induced by pairing SUM and PP stimulation was abolished by lesions of the fimbria–fornix, a major pathway of SUM afferents. SUM stimulation applied 1 s before or after PP stimulation failed to produce E-S potentiation, and SUM stimulation augmented PP–DG field potentials during tetanic stimulation. Furthermore, the E-S potentiation was abolished by blocking GABAergic neurotransmission with picrotoxin. These results suggest that coactivation of SUM and PP inputs produces a long-lasting increase of granule cell excitability by modulating GABAergic inhibition. SUM afferents may contribute to associative memory processing by modulating hippocampal excitability.