A critical role for astrocytes in hypercapnic vasodilation in brain

Cerebral blood flow (CBF) is controlled by arterial blood pressure, arterial CO2, arterial O2, and brain activity and is largely constant in the awake state. Although small changes in arterial CO2 are particularly potent to change CBF (1 mmHg variation in arterial CO2 changes CBF by 3-4%), the coupling mechanism is incompletely understood. We tested the hypothesis that astrocytic prostaglandin E2 (PgE2) plays a key role for cerebrovascular CO2 reactivity and that preserved synthesis of glutathione is essential for the full development of this response. We combined two-photon imaging microscopy in brain slices with in vivo work in rats and C57Bl/6J mice to examine the hemodynamic responses to CO2 and somatosensory stimulation before and after inhibition of astrocytic glutathione and PgE2 synthesis. We demonstrate that hypercapnia (increased CO2) evokes an increase in astrocyte [Ca2+]i and stimulates COX-1 activity. The enzyme downstream of COX-1 that synthesizes PgE2 (microsomal prostaglandin E synthase-1) depends critically for its vasodilator activity on the level of glutathione in the brain. We show that when glutathione levels are reduced, astrocyte calcium-evoked release of PgE2 is decreased and vasodilation triggered by astrocyte [Ca2+]i in vitro and by hypercapnia in vivo is inhibited. Astrocyte synthetic pathways, dependent on glutathione, are involved in cerebrovascular reactivity to CO2. Reductions in glutathione levels in ageing, stroke or schizophrenia could lead to dysfunctional regulation of CBF and subsequent neuronal damage

Amyloid β oligomers constrict human capillaries in Alzheimer's disease via signaling to pericytes

Cerebral blood flow is reduced early in Alzheimer’s disease (AD). Because most of the vascular resistance within the brain is in capillaries, this could reflect dysfunction of contractile pericytes on capillary walls. Here we used live and rapidly-fixed biopsied human tissue to establish disease-relevance, and rodent experiments to define mechanism. We found that, in humans with cognitive decline, amyloid β (Aβ) constricts brain capillaries at pericyte locations. This was caused by Aβ generating reactive oxygen species, which evoked the release of endothelin-1 (ET) that activated pericyte ETA receptors. Capillary, but not arteriole, constriction also occurred in vivo in a mouse model of AD. Thus, inhibiting the capillary constriction caused by Aβ could potentially reduce energy lack and neurodegeneration in AD

Activity-Dependent Calcium, Oxygen, and Vascular Responses in a Mouse Model of Familial Hemiplegic Migraine Type 1

Functional Genomics of Muscle, Nerve and Brain Disorder

Kinetics of Inhibition of Xanthine Oxidase by Lycium arabicum and its Protective Effect against Oxonate- Induced Hyperuricemia and Renal Dysfunction in Mice

Purpose: To evaluate the in-vitro inhibition of xanthine oxidase (purified from bovine milk) by extracts of Lycium arabicum, as well as it is in vivo hypouricemic and renal protective effects.Methods: Four extracts of Lycium arabicum, methanol (CrE), chloroform (ChE), ethyl acetate (EaE) and aqueous (AqE) extracts, were screened for their total phenolics and potential inhibitory effects on purified bovine milk xanthine oxidase (XO) activity by measuring the formation of uric acid or superoxide radical. The mode of inhibition was investigated and compared with the standard drugs, allopurinol, quercitin and catechin. To evaluate their hypouricemic effect, the extracts were administered to potassium oxonate-induced hyperuricemic mice at a dose of 50 mg/kg body weight.Results: The results showed that EaE had the highest content of phenolic compounds and was the most potent inhibitor of uric acid formation (IC50 = 0.017 ± 0.001 mg/mL) and formation of superoxide (IC50 = 0.035 ± 0.001 mg/ml). Lineweaver-Burk analysis showed that CrE and EaE inhibited XO competitively, whereas the inhibitory activities exerted by ChE and AqE were of a mixed type. Intraperetoneal injection of L. arabicum extracts (50 mg/kg) elicited hypouricemic actions in hyperuricemic mice. Hyperuricemic mice presented a serum uric acid concentration of 4.71 ± 0.29 mg/L but this was reduced to 1.78 ± 0.11 mg/L by EaE, which was the most potent hyporuricemic extract.Conclusion: L. arabicum fractions have a strong inhibitory effect on xanthine oxidase and and also have a significantly lowering effect on serum and liver creatinine and urea levels in hyperuricemic mice.Keywords: Lycium arabicum, Uric acid, Creatinine, Superoxide, Phenolic compounds, Flavonoids, Hyperuricemi

Astrocytes contribute to the cerebral blood flow response to hypercapnia

Although astrocyte [Ca2+]i transients can evoke cerebral blood flow (CBF) changes, their role in CBF regulation has been questioned. Based on the signalling pathways which occur within astrocytes, we investigated whether astrocytes contribute to hypercapnia-evoked CBF responses.</p

Astrocytes contribute to the cerebral blood flow response to hypercapnia

Although astrocyte [Ca2+]iandnbsp;transients can evoke cerebral blood flow (CBF) changes, their role in CBF regulation has been questioned. Based on the signalling pathways which occur within astrocytes, we investigated whether astrocytes contribute to hypercapnia-evoked CBF responses.</p