Chronic Exposure to Tramadol Induces Neurodegeneration in the Cerebellum of Adult Male Rats

Ezi, Samira; Boroujeni, Mahdi Eskandarian; Khatmi, Aysan; Vakili, Kimia; Fathi, Mobina; Abdollahifar, Mohammad‐Amin; Aghajanpour, Fakhroddin; Soltani, Reza; Mirbehbahani, Seyed Hamidreza; Khodagholi, Fariba; Aliaghaei, Abbas; Farahani, Reza Mastery

doi:10.1007/s12640-021-00354-w

Cited by 12 publications

(10 citation statements)

References 68 publications

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“…However, the administration of naloxone inhibits neuronal death induced by tramadol. Our findings agree with an in vivo study that administration of tramadol reduced the volume of the striatum (Soltani et al, 2020), the cerebellar motor cortex (Ezi et al, 2021), and the number of pyramidal neurons in the prefrontal cortex (Aghajanpour et al, 2020) of rats. Furthermore, tramadol caused a reduction in the thickness of CA1, CA3 pyramidal cell layer, and granule cell layer of the dentate gyrus of mice (Hussein et al, 2020).…”

Section: Discussionsupporting

confidence: 92%

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Effect of tramadol on apoptosis and synaptogenesis in hippocampal neurons: The possible role of µ‐opioid receptor

Hosseindoost

Akbarabadi

Sadat‐Shirazi

et al. 2022

Drug Development Research

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Tramadol is a synthetic opioid with centrally acting analgesic activity that alleviates moderate to severe pain and treats withdrawal symptoms of the other opioids. Like other opioid drugs, tramadol abuse has adverse effects on central nervous system components. Chronic administration of tramadol induces maladaptive plasticity in brain structures responsible for cognitive function, such as the hippocampus. However, the mechanisms by which tramadol induces these alternations are not entirely understood. Here, we examine the effect of tramadol on apoptosis and synaptogenesis of hippocampal neuronal in vitro. First, the primary culture of hippocampal neurons from neonatal rats was established, and the purity of the neuronal cells was verified by immunofluorescent staining. To evaluate the effect of tramadol on neuronal cell viability MTT assay was carried out. The western blot analysis technique was performed for the assessment of apoptosis and synaptogenesis markers. Results show that chronic exposure to tramadol reduces cell viability of neuronal cells and naloxone reverses this effect. Also, the level of caspase‐3 significantly increased in tramadol‐exposed hippocampal neurons. Moreover, tramadol downregulates protein levels of synaptophysin and stathmin as synaptogenesis markers. Interestingly, the effects of tramadol were abrogated by naloxone treatment. These findings suggest that tramadol can induce neurotoxicity in hippocampal neuronal cells, and this effect was partly mediated through opioid receptors.

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Section: Discussionsupporting

confidence: 92%

“…It has been found that a high dose of tramadol induced toxicity via oxidative damage and mitochondrial dysfunction (Mohammadnejad et al, 2021). In the cerebral cortex, tramadol also increase apoptotic and inflammatory factors (Ezi et al, 2021). However, the mechanisms underlying these changes are not entirely understood.…”

Section: Introductionmentioning

confidence: 99%

Effect of tramadol on apoptosis and synaptogenesis in hippocampal neurons: The possible role of µ‐opioid receptor

Hosseindoost

Akbarabadi

Sadat‐Shirazi

et al. 2022

Drug Development Research

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“…Opioids inhibit the development of precursor neurons of the cerebellar granule layer in rodents and have been observed to promote cell apoptosis and decrease DNA synthesis in rat cerebellum granule layer neuroblasts, according to in vitro studies (Hauser et al 2000 ). This results in detrimental consequences for the survival and differentiation of cerebellar granule cells, essentially impeding signaling events (Ezi et al 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of histological and ultrastructural changes provoked by prenatal tramadol on postnatal cortical cerebellar neuronal development in rats: possible implication of Ki67, GFAP and MicroRNA-7/P53 signalling trajectories

Abdelmoez

2024

J Mol Histol

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Tramadol is a novel centrally acting analgesic. Despite, its implementation during pregnancy may impair neuronal survival and synaptic development in neonatal cerebella. The current investigation assessed the histological and ultrastructural alterations in postnatal cortical cerebellar neuronal development induced by prenatal tramadol. 30 offsprings were divided to control group I: fifteen pups born to mothers given saline from D10 till D21 of gestation. Tramadol-treated group II: fifteen pups born to mothers received tramadol HCL (50 mg/kg/day) from D10 till D21 of gestation. Pups were categorized into three subgroups (a, b, and c) and offered for sacrifice on the seventh, fourteenth and twenty-first post-natal days. Light microscopic examination revealed the overcrowding and signs of red degeneration affecting purkinje cell layer. Neurodegenerative signs of both purkinje and granule cell neurons were also confirmed by TEM in form of chromatin condensation, dilated Golgi channels, disrupted endoplasmic reticulum, marked infolding of the nuclear envelope and decrease in granule cell precursors. In addition, the astrocytic processes and terminal nerve axons appeared with different degrees of demyelination and decreased number of oligodendrocytes and degenerated mitochondria. Furthermore, group II exhibited an increase in P53 immune expression. The area percentage of apoptotic cells detected by TUNEL assay was significantly increased. Besides to the significant decrease of Ki67 immunoreactivity in the stem neuronal cell progenitors. Quantitative PCR results showed a significant decline in micro RNA7 gene expression in tramadol treated groups resulting in affection of multiple target genes in P53 signaling pathways, improper cortical size and defect in neuronal development.

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“…Another report revealed that tramadol treated rats showed atrophy of the cerebellum, microgliosis, neuroinflammation and apoptotic biomarkers (Ezi et al 2021). Tramadol administration during pregnancy caused profound structural abnormalities on the post-natal cerebellar cortex and was also associated with oxidative stress (Aboulhoda and Hassan 2018).…”

Section: Discussionmentioning

confidence: 99%

“…In the brain, chronic administration of tramadol is associated with oxidative stress and cerebral cortex apoptosis (Abdel-Zaher et al 2011;Ghoneim et al 2014). Atrophy of the cerebellum, microgliosis, neuro-inflammation and apoptosis has also been reported (Ezi et al 2021).…”

Section: Introductionmentioning

confidence: 98%

Tramadol and Coffee Synergy Triggered Oxidative Stress, Altered Cerebellar Histomorphology and Behaviour in Rats

Umanah¹,

Umoh²,

Aquaisua³

2023

Nig J Neurosci

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Tramadol intoxication with other substances has recently raised neurological concerns especially among youths in the society. The effects of tramadol and coffee on the cerebellum of Wistar rats were studied. Thirty adult Wistar rats (average weight of 180 g) were randomly assigned into six groups (n=6) as follows: Control, coffee (72.46 mg/kg), coffee (108.69 mg/kg), tramadol (2.86 mg/kg), tramadol (5.71 mg/kg) and coffee (72.46 mg/kg) + tramadol (2.86 mg/kg). The administrations were orally, and done once daily for twenty-eight consecutive days. On day 29, spontane-ous alternation in the T-maze was carried out, and the rats anaesthetized with ketamine hydrochloride (50 mg/kg intraperitoneally). Their blood were assayed for antioxidant, while the 10 % buffered formalin perfused brains were routinely processed with haematoxylin and eosin technique. Behavioural study showed significantly (p<0.05) increased spontaneous alternation in coffee (108.69 mg/kg), tramadol (5.71 mg/kg), and coffee (72.46 mg/kg) + tramadol (2.86 mg/kg) groups compared to the control. Catalase, superoxide dismutase and reduced glutathione levels were not different (p>0.05), while the malondialdehyde level was significantly (p<0.05) higher in the coffee (72.46 mg/kg) + tramadol (2.86 mg/kg) group compared to the control. Histological observations showed cerebellar cytoarchitectural alterations, including atrophy of the Purkinje cells in the coffee (108.69 mg/kg), tramadol (5.71 mg/kg), and coffee (72.46 mg/kg) + tramadol (2.86 mg/kg) groups compared to the control. In conclusion, co-administration of tramadol and coffee triggered free radicals, damaged the cerebellar tissues and caused a more deleterious effect on memory function than individual doses.

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Chronic Exposure to Tramadol Induces Neurodegeneration in the Cerebellum of Adult Male Rats

Cited by 12 publications

References 68 publications

Effect of tramadol on apoptosis and synaptogenesis in hippocampal neurons: The possible role of µ‐opioid receptor

Effect of tramadol on apoptosis and synaptogenesis in hippocampal neurons: The possible role of µ‐opioid receptor

Evaluation of histological and ultrastructural changes provoked by prenatal tramadol on postnatal cortical cerebellar neuronal development in rats: possible implication of Ki67, GFAP and MicroRNA-7/P53 signalling trajectories

Tramadol and Coffee Synergy Triggered Oxidative Stress, Altered Cerebellar Histomorphology and Behaviour in Rats

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