An effective erythropoietin dose regimen protects against severe nerve injury-induced pathophysiological changes with improved neural gene expression and enhances functional recovery

Govindappa, Prem Kumar; Talukder, Milton; Gurjar, Anagha; Hegarty, John P.; Elfar, John C.

doi:10.1016/j.intimp.2020.106330

Cited by 21 publications

(25 citation statements)

References 44 publications

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“…The role of HIF-1␣ is key for the stimulation of EPO prevented tau hyperphosphorylation through the PI3K/Akt-GSK-3␤ pathway in SH-SY5Y cells exposed to the A␤ peptide [149], a mechanism that is also induced by hypoxia and that activate erythropoiesis and glycolysis [150]. 2) LV-hEPO-treated R6/2 mice exhibited reduced hippocampal atrophy, increased neuroblast branching towards the dentate granular cell layer, and improved spatial cognition [169] 3) EPO reduced the cavity ratio, cell apoptosis, and motor neuron loss in the damaged area, but enhanced the autophagy level and extracellular-regulated protein kinase activity [170] 4) Experimental oxygen and/or glucose deprivation stabilized HIF-EPO signaling in cultured astrocytes, and upregulated EPO expression that could suppress neuronal apoptosis [171] 5) Therapeutic dose of EPO to have neuroprotective effects may have to be adjusted to match the fetus increase in size and growth according with the gestation age [172] 6) Exogenous EPO may protect retinal ganglion cells and bipolar cell axon terminals in inner plexiform layer by downregulating apoptotic factors to attenuate NMDA-mediated excitotoxic retinal damage [173] 7) A new EPO carrier "Heparin-binding haemagglutinin adhesion c" was described as a favorable tool for EPO brain delivery and for the applications of EPO in neuroprotection [174] 8) EPO (5000 IU/kg) dose, demonstrated to have an increased sciatic nerve functional recovery by mitigating inflammatory, anti-inflammatory, oxidative stress, angiogenesis, and myelination components of severe sciatic nerve crush injury [175] 9) PEGylated-EPO was more effective than EPO (5,000 U/kg) in the neuroprotective effects on cerebral ischemia damage through anti-oxidant and anti-inflammatory properties by inhibiting NF-κB activation [176] 10) Epo-derived small peptide JM4 that is side-effect free and has strong neuroprotective activity without hematologic effects.…”

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confidence: 99%

Hypoxia, Oxidative Stress, and Inflammation: Three Faces of Neurodegenerative Diseases

Merelli

Repetto

Lazarowski

et al. 2021

JAD

116

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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.

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mentioning

confidence: 99%

Hypoxia, Oxidative Stress, and Inflammation: Three Faces of Neurodegenerative Diseases

Merelli

Repetto

Lazarowski

et al. 2021

JAD

116

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“…Experimental and clinical studies have demonstrated that EPO can function as a neuroprotective molecule by mediating angiogenesis and mitigating oxidative stress, inflammation, and apoptosis 18‐22 . Despite potent neuroprotective effects of EPO in rodent models of PNI, 5,7‐11 investigation into the functional role of EpoR under baseline conditions or with exogenous EPO was not possible because of embryonic lethality of global EPO null and EpoR null mice 23,24 and the lack of selective EpoR antagonists or mice lacking Schwann cell‐specific EpoR .…”

Section: Discussionmentioning

confidence: 99%

Obligatory role of Schwann cell‐specific erythropoietin receptors in erythropoietin‐induced functional recovery and neurogenic muscle atrophy after nerve injury

et al. 2020

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Background Erythropoietin (EPO) promotes myelination and functional recovery in rodent peripheral nerve injury (PNI). While EPO receptors (EpoR) are present in Schwann cells, the role of EpoR in PNI recovery is unknown because of the lack of EpoR antagonists or Schwann cell‐specific EpoR knockout animals. Methods Using the Cre‐loxP system, we developed a myelin protein zero (Mpz) promoter‐driven knockout mouse model of Schwann cell EpoR (MpzCre‐EpoRflox/flox, Mpz‐EpoR‐KO). Mpz‐EpoR‐KO and control mice were assigned to sciatic nerve crush injury followed by EPO treatment. Results EPO treatment significantly accelerated functional recovery in control mice in contrast to significantly reduced functional recovery in Mpz‐EpoR‐KO mice. Significant muscle atrophy was found in the injured hindlimb of EPO‐treated Mpz‐EpoR‐KO mice but not in EPO‐treated control mice. Conclusions These preliminary findings provide direct evidence for an obligatory role of Schwann‐cell specific EpoR for EPO‐induced functional recovery and muscle atrophy following PNI.

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“…EPO is then processed with the removal of a carboxy-terminal arginine 166 in the mature human and recombinant human EPO (rhEPO). A protein of 165 amino acids with a molecular weight of 30.4 kDa is subsequently generated [231][232][233][234]. EPO expression is present in the brain, uterus, and liver, but the primary site for the production and secretion of EPO is the kidney peritubular interstitial cells [229,230,[235][236][237][238].…”

Section: Circadian Clock Genes and The Silent Mating Type Information Regulation 2 Homolog 1 (Saccharomyces Cerevisiae) (Sirt1)mentioning

confidence: 99%

Cognitive Impairment and Dementia: Gaining Insight through Circadian Clock Gene Pathways

Maiese

2021

Biomolecules

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Neurodegenerative disorders affect fifteen percent of the world’s population and pose a significant financial burden to all nations. Cognitive impairment is the seventh leading cause of death throughout the globe. Given the enormous challenges to treat cognitive disorders, such as Alzheimer’s disease, and the inability to markedly limit disease progression, circadian clock gene pathways offer an exciting strategy to address cognitive loss. Alterations in circadian clock genes can result in age-related motor deficits, affect treatment regimens with neurodegenerative disorders, and lead to the onset and progression of dementia. Interestingly, circadian pathways hold an intricate relationship with autophagy, the mechanistic target of rapamycin (mTOR), the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), mammalian forkhead transcription factors (FoxOs), and the trophic factor erythropoietin. Autophagy induction is necessary to maintain circadian rhythm homeostasis and limit cortical neurodegenerative disease, but requires a fine balance in biological activity to foster proper circadian clock gene regulation that is intimately dependent upon mTOR, SIRT1, FoxOs, and growth factor expression. Circadian rhythm mechanisms offer innovative prospects for the development of new avenues to comprehend the underlying mechanisms of cognitive loss and forge ahead with new therapeutics for dementia that can offer effective clinical treatments.

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An effective erythropoietin dose regimen protects against severe nerve injury-induced pathophysiological changes with improved neural gene expression and enhances functional recovery

Cited by 21 publications

References 44 publications

Hypoxia, Oxidative Stress, and Inflammation: Three Faces of Neurodegenerative Diseases

Hypoxia, Oxidative Stress, and Inflammation: Three Faces of Neurodegenerative Diseases

Obligatory role of Schwann cell‐specific erythropoietin receptors in erythropoietin‐induced functional recovery and neurogenic muscle atrophy after nerve injury

Cognitive Impairment and Dementia: Gaining Insight through Circadian Clock Gene Pathways

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