title: Neuroprotection of donepezil against morphine-induced apoptosis is mediated through Toll-like receptors.
abstract: Previously, we had shown that donepezil provides anti-apoptotic effects associated with the prevention of morphine tolerance to the analgesic effect. In this regard, the present study aimed to evaluate the molecular mechanisms involved in this effect considering the possible role of Toll-like receptor (TLR) 2,4, and the balance between pre-apoptotic and anti-apoptotic Bcl family proteins. To this end, male Wistar rats received daily morphine in combination with either normal saline or donepezil (0.5, 1, or 1.5 mg/kg, ip). The analgesic effect was assessed by the plantar test apparatus. The latency was recorded when the animal responded to the light stimulus. On the 15th day, when no significant difference was observed between morphine and saline groups in terms of analgesia, the frontal cortex and lumbar spinal cord of the animals were dissected. Then, TLR2 and 4, Bcl2, and Bax mRNA fold changes were calculated using Real-time PCR method. The results indicated no significant analgesic effect in the morphine group compared with the saline treated animals after 15 days of injection, while daily co-administration of donepezil with morphine preserved significant analgesia. Moreover, Quantitative PCR showed that morphine significantly increased TLRs and Bax gene expressions and decreased the anti-apoptotic Bcl2. In contrast, donepezil prevented these morphine induced changes in the mentioned gene expressions. Taken together, the results suggest that the neuroprotective effects of donepezil in attenuating morphine-induced tolerance and apoptosis are mediated by preventing morphine-induced changes in TLR2 and 4 gene expressions.
authors.affiliation: Student Research Committee, Kurdistan University of Medical Sciences, Sanandaj, Iran.
authors.forename: Alireza
authors.initials: A
authors.lastname: Shafie
authors.affiliation: Student Research Committee, Kurdistan University of Medical Sciences, Sanandaj, Iran.
authors.forename: Farshid
authors.initials: F
authors.lastname: Moradi
authors.affiliation: Cellular and Molecular Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran.
authors.forename: Esmael
authors.initials: E
authors.lastname: Izadpanah
authors.affiliation: Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.
authors.forename: Aram
authors.initials: A
authors.lastname: Mokarizadeh
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.
authors.forename: Mohammad Raman
authors.initials: MR
authors.lastname: Moloudi
authors.affiliation: Cellular and Molecular Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran. Electronic address: nikzabanmehrnoush@gmail.com.
authors.forename: Mehrnoush
authors.initials: M
authors.lastname: Nikzaban
authors.affiliation: Cellular and Molecular Research Center, Kurdistan University of Medical Sciences, Sanandaj, Iran; Department of Physiology and Pharmacology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran. Electronic address: kambizhassanzadeh@gmail.com.
authors.forename: Kambiz
authors.initials: K
authors.lastname: Hassanzadeh
mesh_terms: D000701:Analgesics, Opioid / Q000627:therapeutic use*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000077265:Donepezil; D004361:Drug Tolerance / Q000502:physiology*; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D007189:Indans / Q000494:pharmacology*; D008159:Lumbar Vertebrae; D008297:Male; D009020:Morphine / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010146:Pain / Q000188:drug therapy / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D017208:Rats, Wistar; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000235:genetics
chemical_list: D000701:Analgesics, Opioid; C494828:Bax protein, rat; D007189:Indans; D018696:Neuroprotective Agents; D010880:Piperidines; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051193:Toll-Like Receptors; D051028:bcl-2-Associated X Protein; D009020:Morphine; D000077265:Donepezil
keywords: Apoptosis; Morphine tolerance; Toll-like receptor