Neurodegeneration (NDG) is linked with the progressive loss of neural function with intellectual and/or motor impairment. Several diseases affecting older individuals, including Alzheimer's disease, Amyotrophic Lateral Sclerosis, Huntington’s disease, Parkinson's disease, stroke, Multiple Sclerosis and many others, are the most relevant disorders associated with NDG. Since other pathologies such as refractory epilepsy, brain infections, or hereditary diseases such as “neurodegeneration with brain iron accumulation”, also lead to chronic brain inflammation with loss of neural cells, NDG can be said to affect all ages. Owing to an energy and/or oxygen supply imbal-ance, different signaling mechanisms including MAPK/PI3K-Akt signaling pathways, glutamatergic synapse formation, and/or translocation of phosphatidylserine, might activate some central executing mechanism common to all these pathologies and also related to oxidative stress. Hypoxia inducible factor 1-α (HIF-1α) plays a twofold role through gene activation, in the sense that this factor has to “choose” whether to protect or to kill the affected cells. Most of the afore-mentioned process-es follow a protracted course and are accompanied by progressive iron accumulation in the brain. We hypothesize that the neuroprotective effects of iron chelators are acting against the generation of free radicals derived from iron, and also induce sufficient -but not excessive- activation of HIF-1α, so that only the hypoxia-rescue genes will be activated. In this regard, the expression of the erythropoietin receptor in hypoxic/inflammatory neurons could be the cellular “sign” to act upon by the na-sal administration of pharmacological doses of Neuro-EPO, inducing not only neuroprotection, but eventually, neurorepair as well
The cerebral hypoxia-ischemia can induce a wide spectrum of biologic responses that include depolarization, excitotoxicity, oxidative stress, inflammation, and apoptosis, and result in neurodegeneration. Several adaptive and survival endogenous mechanisms can also be activated giving an opportunity for the affected cells to remain alive, waiting for helper signals that avoid apoptosis. These signals appear to help cells, depending on intensity, chronicity, and proximity to the central hypoxic area of the affected tissue. These mechanisms are present not only in a large list of brain pathologies affecting commonly older individuals, but also in other pathologies such as refractory epilepsies, encephalopathies, or brain trauma, where neurodegenerative features such as cognitive and/or motor deficits sequelae can be developed. The hypoxia inducible factor 1α (HIF-1α) is a master transcription factor driving a wide spectrum cellular response. HIF-1α may induce erythropoietin (EPO) receptor overexpression, which provides the therapeutic opportunity to administer pharmacological doses of EPO to rescue and/or repair affected brain tissue. Intranasal administration of EPO combined with other antioxidant and anti-inflammatory compounds could become an effective therapeutic alternative, to avoid and/or slow down neurodegenerative deterioration without producing adverse peripheral effects.
Ischemic brain injury is a dynamic process that involves oxidative stress, inflammation, and cell death, as well as activation of endogenous adaptive and regenerative mechanisms depending on activation of transcription factors such as hypoxia inducible factor 1-alpha (HIF-1alpha). Because CoCl2 activates HIF-1alpha, we described a new focal-hypoxia model by direct intracerebral CoCl2 injection. Adult male Wistar rats were intracerebrally injected with CoCl2 (2 microl-50 mM), in frontoparietal cortex of right hemisphere, and saline (2 microl) in the contralateral hemisphere. In slides of fixed brains at 1, 6, 9, 24 h or 5 day after treatment, TTC, histochemistry (toluidine blue, Hoescht-33342, TUNEL), immunostaining (HIF-1alpha, GFAP), Lycopersicon esculentum lectin staining, and electron microscopy (EM) were performed. Immediately after 1 h post CoCl2 injection, HIF-1alpha stabilization and neuronal nuclear shrinkage and cromathin condensation were observed by immunostaining and EM, respectively. Neuronal apoptotic nuclear morphology and GFAP immunoreactivity and lectin maximal reactivity were detected during 6-9 h. Ultrastructural alterations of morphology included edematous perinuclear cytoplasm, organelles and endoplasmic reticulum (RE) enlargement, mitochondrial swelling with increased matrix density, and deposits of electron-dense material. Neurons showed particular nuclear indentations. Astrocytes and oligodendrocytes presented alterations in both nuclei and RE with dilated lumen and altered mitochondrias, and all these ultrastructural changes became detectable at day 5. CoCl2 cortical injection mimics focal brain ischemia, inducing neuronal death and glial activation. This model brings the opportunity to develop focal ischemia in selected brain areas to study their functional consequences and potential pharmacological therapies for in vivo models of stroke.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.