Inosine attenuates 3-nitropropionic acid-induced Huntington's disease-like symptoms in rats via the activation of the A2AR/BDNF/TrKB/ERK/CREB signaling pathway

• Published in: Life sciences (1973) 2022-07, Vol.300, p.120569-120569, Article 120569
• Main Authors: El-Shamarka, Marwa El-Sayed, El-Sahar, Ayman E., Saad, Muhammed A., Assaf, Naglaa, Sayed, Rabab H.
• Format: Article
• Language: English
• Subjects: 3-Nitropropionic acid; A2AR; Abnormalities; Adenosine; Animals; Attenuation; Biomarkers; Body weight; Body weight loss; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - metabolism; Complement Factor B - metabolism; Complement Factor B - pharmacology; Cyclic AMP response element-binding protein; Cyclic AMP Response Element-Binding Protein - metabolism; Cytokines; Dementia disorders; Enzyme inhibitors; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - metabolism; Glial fibrillary acidic protein; Glutathione; Huntington Disease - chemically induced; Huntington Disease - drug therapy; Huntington Disease - metabolism; Huntington's disease; Huntingtons disease; IL-1β; Inflammation; Injury analysis; Inosine; Inosine - pharmacology; Interleukins; Kinases; Neostriatum; Neurodegenerative Diseases; Neuronal-glial interactions; Neuroprotection; Neuroprotective Agents - therapeutic use; Neurotoxicity; Nitric oxide; Nitro Compounds; Oxidative stress; PD98059; Propionates - pharmacology; Proteins; Rats; Receptors; SCH58261; Signal Transduction; Signaling; Signs and symptoms; TrkB receptors; Tropomyosin; Tumor necrosis factor-α; Weight loss
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2022.120569

Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disease characterized by involuntary bizarre movements, psychiatric symptoms, dementia, and early death. Several studies suggested neuroprotective activities of inosine; however its role in HD is yet to be elucidated. The current study aimed to demonstrate the neuroprotective effect of inosine in 3-nitropropionic acid (3-NP)-induced neurotoxicity in rats while investigating possible underlying mechanisms. Rats were randomly divided into five groups; group 1 received i.p. injections of 1% DMSO, whereas groups 2, 3, 4, and 5 received 3-NP (10 mg/kg, i.p.) for 14 days, concomitantly with inosine (200 mg/kg., i.p.) in groups 3, 4, and 5, SCH58261, a selective adenosine 2A receptor (A2AR) antagonist, (0.05 mg/kg, i.p.) in group 4, and PD98059, an extracellular signal-regulated kinase (ERK) inhibitor, (0.3 mg/kg, i.p.) in group 5. Treatment with inosine mitigated 3-NP-induced motor abnormalities and body weight loss. Moreover, inosine boosted the striatal brain-derived neurotrophic factor (BDNF) level, p-tropomyosin receptor kinase B (TrKB), p-ERK, and p-cAMP response element-binding protein (CREB) expression, which subsequently suppressed oxidative stress biomarkers (malondialdehyde and nitric oxide) and pro-inflammatory cytokines (tumor necrosis factor alpha and interleukin-1β) and replenished the glutathione content. Similarly, histopathological analyses revealed decreased striatal injury score, the expression of the glial fibrillary acidic protein, and neuronal loss after inosine treatment. These effects were attenuated by the pre-administration of SCH58261 or PD98059. In conclusion, inosine attenuated 3-NP-induced HD-like symptoms in rats, at least in part, via the activation of the A2AR/BDNF/TrKB/ERK/CREB signaling pathway. [Display omitted]