Oxidative stress/PERK/apoptotic pathways interaction contribute to tramadol neurotoxicity in rat cerebral and cerebellar cortex and thyme enhances the antioxidant defense system: histological, immunohistochemical and ultrastructural study

Abstract

<p class="abstract"><strong>Background:</strong> Tramadol is an opioid analgesic with several adverse reactions. Oxidative and endoplasmic reticulum (ER) stresses have been involved in the molecular mechanisms underlying tramadol neurotoxicity. Importantly, protein kinase RNA-like ER kinase (PERK) is a key ER-downstream pathway that mediates apoptosis. We aimed to determine the cellular stresses interaction that mediates PERK-induced apoptosis in tramadol-treated rats and to assess the effect of thyme in enhancing the antioxidant defense system in the face of such stresses.</p><p class="abstract"><strong>Methods:</strong> Forty male Sprague Dawley rats were randomized into 4 groups. Control group, thyme group received thyme extract (500 mg/kg/day) orally. Tramadol group received tramadol HCL (40 mg/Kg/day) dissolved in saline orally. Tramadol + Thyme group received tramadol and thyme extract. After 30 days, frontal motor and cerebellar cortex specimens were biochemically assessed for oxidative stress biomarkers and evaluated for histological, ultrastructural and immunohistochemical changes. </p><p class="abstract"><strong>Results:</strong> Tramadol group showed a significant elevation in malondialdehyde level with a reduction in superoxide dismutase and catalase enzyme activities. Histologically and ultrastructurally, there were remarkable degenerative and apoptotic changes in the neurons and glial cells. In parallel, we detected a significant increase in integrated density for PERK immunostaining and number of caspase-3 positive cells/HPF compared to control. Tramadol + Thyme group showed improvement in oxidative stress parameters, histological and ultrastructural changes. Moreover, integrated density for PERK immunostaining and number of caspase-3 positive cells/HPF were significantly lower than Tramadol group.</p><p class="abstract"><strong>Conclusions:</strong> Oxidative and ER stress-mediated PERK/apoptosis axis corroborates to the tramadol-induced neurotoxicity. Therapeutic strategies enhancing antioxidant activity and/or blocking ROS-mediated ER stress pathway may resolve tramadol neurotoxicity.</p>

Histological and immunohistochemical study of the effects of tramadol administration on the ovaries of adult albino rats and the possible recovery after its Withdrawal.

“…In this study the observed dilated congested blood capillaries could be explained by the vasodilatory effect of the produced nitric oxide [35] . Abdel-Zaher et al, 2011 [36] found that tramadol administration for consecutive days increased nitric oxide levels in the brain which played a critical role in the development of the ovarian follicles, function of the corpus luteam and ovulation [37] .…”

Effects of tramadol administration on male reproductive toxicity in Wistar rats The role of oxidative stress, mitochondrial dysfunction, apoptosis-related gene expression, and nuclear factor kappa B signalling

“…In 2016, the National Survey on Drug Use and Health (NS-DUH) reported that 1.6 million people over the age of 12 years used Tra for non-medical reasons in the United States (2). In previous reports, a wide range of side effects has been attributed to Tra consumption, including histopathological and biochemical damage to the liver, kidneys, testis (4-6) and brain of rats (7). According to previous studies, several mechanisms are involved in Tra-induced toxicity, such as oxidative stress (5,8) and cell death (9).…”

Tramadol-Induced Organ Toxicity via Oxidative Stress : A Review Study

“…The experimental studies indicated that the chronic TR administration altered neurotransmitter levels and oxidative stress in the brain [20,[24][25][26][27]. For example, in an experimental study, chronic tramadol administration (30 or 60 mg/kg via oral gavage; for 8 weeks) revealed a significantly increased lipid peroxidation and NO, and decreased GSH level and antioxidant enzymes activity and expression in the cerebrum.…”

“…Besides, the ultrastructural changes of mitochondria and cytoskeletal structure with the disruption of oxidative damage, apoptosis, energy metabolism, and signal transduction pathways were determined [26]. Raj et al suggested that the long-term administration of TR in rats (50 mg/kg, intraperitoneal injection for 28 days) altered oxidative stress markers (including lipid peroxidation, nitrite, GSH, Glutathione Peroxidase (GPx) activity, SOD, CAT, mitochondrial complex I, IV, and cyclic Adenosine Monophosphate (cAMP)), neuroinflammatory markers (TNF-α, IL-1β, and IL-17), and neurotransmitters (dopamine, norepinephrine, serotonin, GABA, and glutamate) in rats brain (striatum) leads to motor deficits [27].…”