Abstract
3-Nitropropionic acid (3-NP) model serves as a beneficial tool to evaluate the effect of novel treatments for Huntington’s disease (HD). The aim of the present study was to demonstrate the neuroprotective effect of recombinant human erythropoietin (rhEPO) and interferon-beta-1b (IFN-β-1b) in 3-NP-induced neurotoxicity in rats. Rats were injected with 3-NP (10 mg/kg/day, i.p) for 2 weeks and were divided into five subgroups; the first served as the HD group, the second received rhEPO (5000 IU/kg/every other day, i.p.) for 2 weeks, the third received rhEPO starting from the 5th day of 3-NP injection, the fourth received IFN-β-1b (300,000 units, every day other day, s.c) for 2 weeks, and the last received IFN-β-1b starting from the 5th day of 3-NP injection. All treatments significantly improved motor and behavior performance of rats. Moreover, all treatments markedly restored mitochondrial function as well as brain-derived neurotrophic factor level, and reduced oxidative stress biomarkers, pro-inflammatory mediators, nuclear factor kappa B expression, caspase-3, and Bax/Bcl2 ratio in the striatum. In conclusion, the present study demonstrates the neuroprotective potential of rhEPO or IFN-β-1b on 3-NP-induced neurotoxicity in rats. Furthermore, our study suggests that activation of JAK2/STAT3 or JAK1/STAT3 may contribute to the neuroprotective activity of rhEPO or IFN-β-1b, respectively. We also found that early treatment with rhEPO did not confer any benefits compared with late rhEPO treatment, while early IFN-β-1b showed a marked significant benefit compared with late IFN-β-1b.
Highlights
Huntington’s disease (HD) is an incurable autosomal dominant progressive neurodegenerative disease characterized by neuronal degeneration in the striatum and is associated with involuntary movements, cognitive deficits, and psychiatric disturbances (Ayala-Peña 2013; Ramaswamy et al 2015). 3-Nitropropionic acid (3-NP) is a natural mycotoxin that can readily pass the blood–brain barrier (BBB) and induces dystonic movements and cognitive impairments resembling that of human HD (Kaur et al 2015). 3-NP causes irreversible inhibition of mitochondrial complex II enzyme, succinate
Recombinant human erythropoietin is a 165amino acid glycoprotein that is widely used for treatment of different types of anemia (Fisher 2003). recombinant human erythropoietin (rhEPO) has emerged as a neuroprotective agent against numerous types of central nervous system (CNS) insults
Interferon type I receptor (IFNAR) activation by IFN-β induces STAT3 phosphorylation and subsequently inhibits inflammation and apoptosis (Dixon et al 2016; Bolívar et al 2018). Respecting to these findings, the aim of the current study was to demonstrate the neuroprotective effect of rhEPO and IFN-β-1b in 3-NP-induced neurotoxicity and to investigate the potential underlying mechanisms. rhEPO or IFN-β in our study was given according to two different treatment regimens: either starting at the day of disease onset to reflect the clinical situation or at the day of first 3-NP injection as a prophylactic treatment
Summary
Huntington’s disease (HD) is an incurable autosomal dominant progressive neurodegenerative disease characterized by neuronal degeneration in the striatum and is associated with involuntary movements, cognitive deficits, and psychiatric disturbances (Ayala-Peña 2013; Ramaswamy et al 2015). 3-Nitropropionic acid (3-NP) is a natural mycotoxin that can readily pass the blood–brain barrier (BBB) and induces dystonic movements and cognitive impairments resembling that of human HD (Kaur et al 2015). 3-NP causes irreversible inhibition of mitochondrial complex II enzyme, succinateRecombinant human erythropoietin (rhEPO) is a 165amino acid glycoprotein that is widely used for treatment of different types of anemia (Fisher 2003). rhEPO has emerged as a neuroprotective agent against numerous types of central nervous system (CNS) insults. Binding of EPO to its receptor induces a conformational change, initiating EPORassociated janus kinase 2 (JAK2) tyrosine phosphorylation and multiple downstream signaling cascades including signal transducers and activators of transcription (STATs) and nuclear factor kappa B (NF-κB) (Parganas et al 1998; Ott et al 2015). Activation of these signaling cascades leads to up-regulation of anti-apoptotic and neuroprotective genes (Digicaylioglu and Lipton 2001; Zhao et al 2011)
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