title: ADIOL protects against 3-NP-induced neurotoxicity in rats: Possible impact of its anti-oxidant, anti-inflammatory and anti-apoptotic actions.
abstract: Huntington's disease (HD) is a progressive neurodegenerative disorder with a wide spectrum of cognitive, behavioral and motor abnormalities. The mitochondrial toxin 3-nitropropionic acid (3-NP) effectively induces specific behavioral changes and selective striatal lesions similar to that observed in HD. Some neurosteroids, synthesized in neurons and glial cells, previously showed neuroprotective abilities. 5-Androstene-3β-17β-diol (ADIOL) is a major metabolite of dehydroepiandrosterone (DHEA) with previously reported anti-inflammatory, anti-apoptotic and neuroprotective activities. The neuroprotective potential of ADIOL in HD was not previously investigated. Therefore, the present study investigated the neuroprotective effects of ADIOL against 3-NP-induced behavioral changes, oxidative stress, inflammation and apoptosis. Intraperitoneal administration of 3-NP (20mg/kg) for 4 consecutive days in rats caused significant loss in body weight, reduced prepulse inhibition (PPI) of acoustic startle response, locomotor hypoactivity with altered cortical/striatal histological structure, increased cortical/striatal oxidative stress, inflammation and apoptosis. Administration of ADIOL (25mg/kg, s.c.) for two days before 3-NP significantly attenuated the reduction in body weights and PPI, increased locomotor activity and restored cortical/striatal histological structure nearly to normal. Moreover, it displayed anti-oxidant, anti-inflammatory and anti-apoptotic activities as evidenced by the elevation of cortical and striatal reduced glutathione levels, reductions of cortical and striatal malondialdehyde, striatal tumor necrosis factor alpha and interleukin-6 levels. Only a small number of iNOS and caspase-3 positive cells were detected in sections from rats pretreated with ADIOL. This study suggests a potential neuroprotective role of ADIOL against 3-NP-induced Huntington's disease-like manifestations. Such neuroprotection can be attributed to its anti-oxidant, anti-inflammatory and anti-apoptotic activities.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
authors.forename: Diana M F
authors.initials: DM
authors.lastname: Hanna
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt. Electronic address: mirogeogo@yahoo.com.
authors.forename: Mariane G
authors.initials: MG
authors.lastname: Tadros
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
authors.forename: Amani E
authors.initials: AE
authors.lastname: Khalifa
mesh_terms: D000704:Analysis of Variance; D000735:Androstenedione / Q000627:therapeutic use*; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005978:Glutathione / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000517:prevention & control*; D009498:Neurotoxins / Q000633:toxicity*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009574:Nitro Compounds / Q000633:toxicity*; D011422:Propionates / Q000633:toxicity*; D051381:Rats; D013216:Reflex, Startle / Q000187:drug effects
chemical_list: D000975:Antioxidants; D016207:Cytokines; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; D000735:Androstenedione; D008315:Malondialdehyde; C003528:5-androstene-3,17-dione; D002374:Catalase; D052247:Nitric Oxide Synthase Type II; D053148:Caspase 3; D005978:Glutathione; C015392:3-nitropropionic acid
keywords: 3-Nitropropionic acid; ADIOL; Apoptosis; Neuroinflammation; Prepulse inhibition