Cerebral hypoperfusion..."Decreased blood flow may contribute to the pathology of MS..." click here
The orthodox theory of MS is that it is an "autoimmune disorder," meaning that the immune system is attacking intact (normal) myelin. This theory has never been proven. Zamboni's CCSVI theory proposes that abnormally low brain perfusion is at the heart of damage to oligodendrocytes and myelin, possibly due to oxidative stress (excessive free radicals). Although much of the focus by neurologists has been on the problematic use of ultrasound to detect abnormalities in the internal jugular veins our attention should in fact be on measuring brain perfusion.
This paper uses arterial spin-labelling to measure brain perfusion. These authors and several others found that perfusion is indeed abnormally low in MS. Traditionally this hypoperfusion has been attributed to damaged brain cells, the idea being that perfusion is reduced because the damaged brain does not need as much perfusion. But this paper demonstrates that perfusion can be returned to normal by injection of bosentan, a vasodilator.
At this point the missing pieces are to demonstrate that obstructions of brain draining veins are correlated with brain hypoperfusion and to find ways to improve perfusion and reduce oxidative stress. We are excited about the evidence that Nrf2 activator anti-oxidants such as Tecfidera, but also the supplement Protamdin have been proven effective for MS and are committed to continue the study of the role of venoplasty in improving perfusion.
3. Hypoxia and Iron Metabolism
The profound effects of hypoxia on organismal iron metabolism have been well described. Early studies demonstrated that hypoxia affected dietary iron absorption [30–32] and increased erythropoiesis when humans were moved from sea level to high altitude . As the partial pressure of O2 decreases through increased elevation, anemia, or localized tissue hypoxia, a battery of genes are induced by the hypoxia inducible factor (HIF)/hypoxia response element (HRE) system. The HIF system senses O2 levels through degradation of HIF transcription factors (HIF-1α and HIF-2α) that are mediated by the partial pressure of O2 and iron-dependent hydroxylases. At normoxic O2 tensions, HIF-1α is hydroxylated by prolyl hydroxylase and then bound by the von Hippel-Lindau (VHL) protein leading ultimately to ubiquitination and proteasome degradation. During hypoxic conditions, the activity of hydroxylases is inhibited allowing HIF-1α to accumulate and bind along with HIF-1β to HRE found in the promoters of target genes. Similar to HIF-1α, HIF-2α stability is mediated by the partial pressure of O2 through prolyl hydroxylase and plays a dominant role in hypoxic signaling of EPO expression . ]
Endothelin-1 (ET1) is a potent vasoconstrictor peptide implicated in the cerebrovascular alterations occurring in stroke, subarachnoid hemorrhage, and brain trauma. Brain or circulating levels of ET1 are elevated in these conditions and in risk factors for cerebrovascular diseases. Most studies on the cerebrovascular effects of ET1 have focused on vascular smooth muscle constriction, and little is known about the effect of the peptide on cerebrovascular regulation. We tested the hypothesis that ET1 increases cerebrovascular risk by disrupting critical mechanisms regulating cerebral blood flow. Male C57Bl6/J mice equipped with a cranial window were infused intravenously with vehicle or ET1, and somatosensory cortex blood flow was assessed by laser Doppler flowmetry. ET1 infusion increased mean arterial pressure and attenuated the blood flow increase produced by neural activity (whisker stimulation) or neocortical application of the endothelium-dependent vasodilator acetylcholine but not A23187. The cerebrovascular effects of ET1 were abrogated by the ET(A) receptor antagonist BQ123 and were not related to vascular oxidative stress. Rather, the dysfunction was dependent on Rho-associated protein kinase activity. Furthermore, in vitro studies demonstrated that ET1 suppresses endothelial nitric oxide (NO) production, assessed by its metabolite nitrite, an effect associated with Rho-associated protein kinase-dependent changes in the phosphorylation state of endothelial NO synthase. Collectively, these novel observations demonstrate that increased ET1 plasma levels alter key regulatory mechanisms of the cerebral circulation by modulating endothelial NO synthase phosphorylation and NO production through Rho-associated protein kinase. The ET1-induced cerebrovascular dysfunction may increase cerebrovascular risk by lowering cerebrovascular reserves and increasing the vulnerability of the brain to cerebral ischemia.
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