jimmylegs wrote:reminds me of what my neuro said about elevated uric acid, anon. i didn't get it at the time but it does make sense now (as one of many consequences of poor nutrient status, zinc in particular).
this was interesting:
Enhancement of social isolation-induced aggressive behavior of young mice by zinc deficiency. (2008)
Neuropsychological behavior via activation of the hypothalamic-pituitary-adrenal (HPA) axis was analyzed using young mice fed a zinc-deficient diet for 2 weeks. Serum corticosterone concentration was significantly increased after 2-week zinc deprivation, whereas zinc concentration in the brain was not decreased. In the resident-intruder test, the rate of mice that exhibited aggressive behavior to the total mice was significantly higher in isolated zinc-deficient mice than in isolated control mice. The duration of aggressive behavior was more in isolated zinc-deficient mice. These results indicate that aggressive behavior of young mice elicited by social isolation is enhanced by zinc deficiency. On the other hand, social isolation-induced aggressive behavior was enhanced in isolated pair-fed mice with food restriction that can activate the HPA axis. Serum corticosterone concentration was also significantly higher in isolated zinc-deficient mice. To see the effect of the increased serum corticosterone on behavioral abnormality, neurotransmitter concentrations in brain tissue were checked. The concentrations of glutamate and GABA in brain tissue were significantly higher in both grouped and isolated zinc-deficient mice. Furthermore, the concentration of extracellular glutamate in the amygdala before the resident-intruder test was significantly higher in isolated zinc-deficient (aggressive) mice and the higher concentration was maintained during the test. The changes in neurotransmitter homeostasis, probably via the increase in serum corticosterone, seem to be linked to aggressive behavior elicited by social isolation in zinc deficiency
Zinc is concentrated in certain CNS excitatory tracts, especially in hippocampal mossy fibres where it has been suggested to modulate synaptic transmission and plasticity. Using rat mossy fibre synaptosomes depolarized by 4-aminopyridine, we show here that low zinc concentrations restore the membrane potential and reduce glutamate release. Both effects arose from activation of ATP-sensitive potassium channels (KATP), since they were mimicked by the KATP opener diazoxide and antagonized by the KATP blocker tolbutamide. Using recombinant channels expressed in COS-7 cells, we confirmed that micromolar zinc did activate KATP of the type found in hippocampus. We tested the hypothesis that this action of zinc could be beneficial during an ischaemic challenge by using organotypic hippocampal slice cultures. When zinc was applied at micromolar concentrations during a brief anoxic-hypoglycaemic episode, it significantly attenuated the ensuing neuronal death, whereas chelation of endogenous zinc markedly aggravated cell damage. Protective effect of zinc was mediated through KATP, as was shown by using the opener diazoxide and the blocker tolbutamide. Thus, by activating pre-synaptic KATP channels, zinc protects neurones from hyper-excitation, excessive transmitter release and exitotoxicity, and may thus act as an endogenous neuroprotector in conditions such as epilepsy or stroke.
Approximately 10% of total zinc in the brain exists in synaptic vesicles of glutamatergic neurons; however, the function of vesicular zinc is poorly understood. The presynaptic action of zinc against excitatory and inhibitory neurotransmission was studied in rat hippocampus using in vivo microdialysis. When the hippocampal CA3 region was perfused with 10–300 μM ZnCl2, the level of glutamate in the perfusate was decreased, whereas the level of γ-aminobutyric acid (GABA) was increased. Chelation of endogenous zinc with CaEDTA increased the glutamate level in the perfusate but decreased the GABA level, suggesting that zinc released into the synaptic cleft acts differentially on glutamatergic and GABAergic neurons in the CA3 region. The increase of GABA level by zinc was antagonized by 2,3-dioxo-6-nitro-1,2.3,4-tetrahydrobenzo(f)quinoxaline-7-sulphonamide (NBQX), an antagonist of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate receptors, but not affected by MK801, an antagonist of N-methyl-d-aspartate (NMDA) receptors, and verapamil, a blocker of voltage-dependent calcium channels. The present study suggests that zinc enhances GABA release via potentiation of AMPA/kainate receptors in the CA3 region, followed by a decrease in presynaptic glutamate release in the same region. Zinc seems to be an inhibitory neuromodulator of glutamate release. © 2003 Wiley-Liss, Inc.
Zinc ions highly concentrate in hippocampus and play a key role in modulating spatial learning and memory. At a time when dietary fortification and supplementation of zinc have increased the zinc consuming level especially in the youth, the toxicity of zinc overdose on brain function was underestimated. In the present study, weaning ICR mice were given water supplemented with 15 ppm Zn (low dose), 60 ppm Zn (high dose) or normal lab water for 3 months, the behavior and brain zinc homeostasis were tested. Mice fed high dose of zinc showed hippocampus-dependent memory impairment. Unexpectedly, zinc deficiency, but not zinc overload was observed in hippocampus, especially in the mossy fiber-CA3 pyramid synapse. The expression levels of learning and memory related receptors and synaptic proteins such as NMDA-NR2A, NR2B, AMPA-GluR1, PSD-93 and PSD-95 were significantly decreased in hippocampus, with significant loss of dendritic spines. In keeping with these findings, high dose intake of zinc resulted in decreased hippocampal BDNF level and TrkB neurotrophic signaling. At last, increasing the brain zinc level directly by brain zinc injection induced BDNF expression, which was reversed by zinc chelating in vivo. These results indicate that zinc plays an important role in hippocampus-dependent learning and memory and BDNF expression, high dose supplementation of zinc induces specific zinc deficiency in hippocampus, which further impair learning and memory due to decreased availability of synaptic zinc and BDNF deficit.
Our results indicated that Zn treatment showed proconvulsant activity and increased BBB permeability, possibly changing prooxidant/antioxidant balance and neuronal excitability during seizures.
Zinc deficiency causes abnormal glucocorticoid secretion and increases depression-like behavior in animals. Neuropsychological symptoms are observed prior to the decrease in Zn2+ signal in the hippocampus under zinc deficiency. This paper summarizes that hippocampal Zn2+ signaling serves to maintain healthy brain and that glucocorticoid signaling, which is responsive to zinc homeostasis in the living body, is linked to the pathophysiology of depression.
Angiotensin II type 1 (AT(1)) receptors are expressed within organs of the hypothalamo-pituitary-adrenal (HPA) axis and seem to be important for its stress responsiveness. Secretion of CRH, ACTH, and corticosterone (CORT) is increased by stimulation of AT(1) receptors. In the present study, we tested whether a blockade of the angiotensin II system attenuates the HPA axis reactivity in spontaneously hypertensive rats. Spontaneously hypertensive rats were treated with candesartan (2 mg/kg), ramipril (1 mg/kg), or mibefradil (12 mg/kg) for 5 wk. In addition to baseline levels, CORT and ACTH responses to injection of CRH (100 microg/kg) were monitored over 4 h. mRNA of CRH, proopiomelanocortin, AT(1A), AT(1B), and AT(2) receptors was quantified by real-time PCR. All treatments induced equivalent reductions of blood pressure and had no effect on baseline levels of CORT and ACTH. However, both candesartan and ramipril significantly reduced CRH-stimulated plasma levels of ACTH (-26 and -15%) and CORT (-36 and -18%) and lowered hypothalamic CRH mRNA (-25 and -29%). Mibefradil did not affect any of these parameters. Gene expression of AT(1A), AT(1B), and AT(2) receptors within the HPA axis was not altered by any drug. We show for the first time that antihypertensive treatment by inhibition of AT(1) receptors or angiotensin-converting enzyme attenuates HPA axis reactivity independently of blood pressure reduction. This action is solely evident after CRH stimulation but not under baseline conditions. Both a reduced pituitary sensitivity to CRH and a down-regulation of hypothalamic CRH expression have the potential to reduce HPA axis activity during chronic AT(1) blockade or angiotensin-converting enzyme inhibition.
The protein, pigment epithelium-derived factor (PEDF), has well-known anti-tumor generating properties. But its role in promoting growth of a type of brain cell and regenerating the protective myelin sheaths around nerve cells had not been known, the researchers say.
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“Our investigation found that PEDF plays a key role in accelerating regeneration of the myelin sheath,” says study senior author David Pleasure, professor of neurology and pediatrics, and director of the Institute for Pediatric Regenerative Medicine, a collaborative initiative of the University of California, Davis, School of Medicine and Shriners Hospitals for Children Northern California.
“That makes PEDF a strong drug-therapy candidate, because it appears to encourage the regeneration of a type of brain cell called oligodendocyte and is able to repair the damage caused by demyelinative diseases, including MS.”
Significance of pigment epithelium-derived factor levels with angiotensin II type 1 receptor blockers in patients with successful coronary stent implantation.
Sugihara M, Miura S, Takamiya Y, Kiya Y, Arimura T, Iwata A, Kawamura A, Nishikawa H, Yamagishi S, Saku K.
Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan.
Pigment epithelium-derived factor (PEDF) and pentosidine have received growing attention as sensitive biomarkers of the progression of atherosclerosis. The present study was performed to evaluate the utility of these biomarkers for assessing the effects of angiotensin II type 1 receptor blockers (ARBs). Sixty-three patients with coronary artery disease (CAD) following successful stent implantation were divided into an ARB group (n = 50), who initially received valsartan or olmesartan immediately following stent implantation, and a non-ARB group (n = 13) according to their blood pressure (BP) at baseline. Measurement of BP and blood sampling was performed prior to (at baseline) and 6-8 months following stent implantation (at follow-up). There were no significant differences in the baseline characteristics between the groups. Although there were no differences in the percentage of diameter re-stenosis between the groups, the BP level in the ARB group at follow-up showed a significant reduction and reached the target BP. The levels of plasma PEDF were significantly increased at follow-up in the ARB group, but not in the non-ARB group, while there were no differences in the levels of pentosidine between the groups. Changes in BP (ΔBP = BP at follow-up minus BP at baseline) were not associated with ΔPEDF. In conclusion, PEDF may be a useful biomarker for assessing the effects of ARBs independent of a reduction in BP.
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