title: Lipoic acid and pentoxifylline mitigate nandrolone decanoate-induced neurobehavioral perturbations in rats via re-balance of brain neurotransmitters, up-regulation of Nrf2/HO-1 pathway, and down-regulation of TNFR1 expression.
abstract: Behavioral perturbations associated with nandrolone decanoate abuse by athletes and adolescents may be attributed to oxidative stress and inflammation. However, the underlying mechanisms are not yet fully explored. On the other hand, the natural antioxidant lipoic acid can pass the blood brain barrier and enhance Nrf2/HO-1 (nuclear factor erythroid-2 related factor 2/heme oxygenase-1) pathway. In addition, the phosphodiesterase-IV inhibitor xanthine derivative pentoxifylline has a remarkable inhibitory effect on tumor necrosis factor-alpha (TNF-α). Therefore, this study aimed at investigation of the possible protective effects of lipoic acid and/or pentoxifylline against nandrolone-induced neurobehavioral alterations in rats. Accordingly, male albino rats were randomly distributed into seven groups and treated with either vehicle, nandrolone (15mg/kg, every third day, s.c.), lipoic acid (100mg/kg/day, p.o.), pentoxifylline (200mg/kg/day, i.p.), or nandrolone with lipoic acid and/or pentoxifylline. Rats were challenged in the open field, rewarded T-maze, Morris water maze, and resident-intruder aggression behavioral tests. The present findings showed that nandrolone induced hyperlocomotion, anxiety, memory impairment, and aggression in rats. These behavioral abnormalities were accompanied by several biochemical changes, including altered levels of brain monoamines, GABA, and acetylcholine, enhanced levels of malondialdehyde and TNF-α, elevated activity of acetylcholinesterase, and up-regulated expression of TNF-α receptor-1 (TNFR1). In addition, inhibited catalase activity, down-regulated Nrf2/HO-1 pathway, and suppressed acetylcholine receptor expression were observed. Lipoic acid and pentoxifylline combination significantly mitigated all the previously mentioned deleterious effects mainly via up-regulation of Nrf2/HO-1 pathway, inhibition of TNF-α and down-regulation of TNFR1 expression. In conclusion, the biochemical and histopathological findings of this study revealed the protective mechanisms of lipoic acid and pentoxifylline against nandrolone-induced behavioral changes and neurotoxicity in rats.
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Misr University for Science and Technology (MUST), 6th of October City, Giza, Egypt. Electronic address: mahapharm@yahoo.com.
authors.forename: Maha A E
authors.initials: MA
authors.lastname: Ahmed
authors.affiliation: Department of Pharmacology, National Research Center, Dokki, Giza, Egypt.
authors.forename: Sally A
authors.initials: SA
authors.lastname: El-Awdan
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000378:metabolism; D008297:Male; D001523:Mental Disorders / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009277:Nandrolone / Q000009:adverse effects / Q000031:analogs & derivatives*; D000077603:Nandrolone Decanoate; D018696:Neuroprotective Agents / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D010431:Pentoxifylline / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D008063:Thioctic Acid / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; D018377:Neurotransmitter Agents; D047888:Receptors, Tumor Necrosis Factor, Type I; C506237:Tnfrsf1a protein, rat; D009277:Nandrolone; D008063:Thioctic Acid; D051547:Heme Oxygenase-1; D000077603:Nandrolone Decanoate; D000109:Acetylcholine; D010431:Pentoxifylline
keywords: AchR; Brain neurotransmitters; Lipoic acid; Morris water maze; Nandrolone decanoate; Nrf2/HO-1 pathway; Open field; Pentoxifylline; Resident–intruder aggression test; TNFR1