Apoptotic inducement of neuronal cells by codeine: possible role of disrupted redox state and caspase 3 signaling

Ajayi, Ayodeji Folorunsho; Akhigbe, R.E.

doi:10.1016/j.heliyon.2021.e07481

Cited by 8 publications

(5 citation statements)

References 40 publications

(71 reference statements)

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“…This result indicates that codeine is an endocrine disruptor and induces reproductive toxicity [ 2 , 4 , 19 ]. The observation that codeine did not alter body weight in this study agrees with our previous studies that reported the sparing effect of codeine on body weight [ 24 – 26 ]. Although there are no previous studies on the effect of codeine on AGD and AGI, Slamberova et al [ 27 ] demonstrated that morphine, an opioid like codeine, reduced AGD.…”

Section: Discussionsupporting

confidence: 93%

L-Arginine reverses maternal and pre-pubertal codeine exposure-induced sexual dysfunction via upregulation of androgen receptor gene and NO/cGMP signaling

2022

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Background Although codeine has been reported to enhance sexual activity by improving penile reflexes, it has been shown to impair fertility indices. Also, codeine impairs ovarian steroidogenesis and folliculogenesis. Nonetheless, whether or not codeine exerts an epigenetic effect remains unclear. On the other hand, arginine has been speculated to enhance penile reflexes by upregulating NO/cGMP Signaling. Aim The study evaluated the effect of maternal codeine exposure and prepubertal codeine and arginine treatments on F1 male sexual function and fertility indices, as well as the outcome of F2 progenies. In addition, the epigenetic programming mechanism was also explored. Methods Forty three-week-old female rats were randomized into two groups (n = 20 rats/group); the control that received 0.5 ml of distilled water and the codeine-treated that received 5 mg/kg of codeine via gavage for eight weeks. Afterward, the female rats were paired for mating with sexually mature male rats. Rats were maintained on their pre-pregnancy treatments throughout pregnancy and lactation. FI progenies from each cohort (control and codeine-treated cohorts) were weaned at three weeks and randomized into four groups; the control, codeine-treated, L-arginine-treated (300mg/kg), and codeine + L-arginine-treated (n = 10 rats/group). Administration commenced a week post-weaning and lasted for eight weeks via gavage. Key findings Maternal codeine exposure did not alter body weight, but significantly reduced anogenital distance and anogenital index of F1 male offspring. Also, maternal codeine delayed preputial membrane separation, impaired male sexual competence, and penile reflexes of F1 male offsprings. These were associated with reduced dopamine, gonadotropins, and testosterone levels as well as suppressed expression of androgen receptor mRNA. In addition, maternal codeine downregulated NO/cGMP signaling, impaired fertility indices, and reduced the litter size, weight, and survival of F2 progenies. These alterations were observed to be aggravated by prepubertal codeine exposure but improved by prepubertal arginine treatment. Significance In conclusion, codeine programmed sexual dysfunction by suppressing the levels of dopamine and testosterone, as well as repressing the expression of androgen receptor mRNA. In addition, codeine-induced epigenetic reprogramming was expressed in the F2 offsprings as reduced litter size and weight, and survival rate. Notably, these observations were worsened by prepubertal codeine exposure, but dampened by prepubertal arginine treatment.

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Section: Discussionsupporting

confidence: 93%

L-Arginine reverses maternal and pre-pubertal codeine exposure-induced sexual dysfunction via upregulation of androgen receptor gene and NO/cGMP signaling

2022

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“…While we showed similar effects of two different opioid agonists, morphine and DAMGO, it remains possible that not all opioid agonists would act similarly. However, previous studies have demonstrated that methadone and codeine induce increases in ROS levels [ 81 , 82 ]. Furthermore, our investigations were limited to the study of endolysosomes, mitochondria and the cytosol.…”

Section: Discussionmentioning

confidence: 99%

Mu opioid receptor-mediated release of endolysosome iron increases levels of mitochondrial iron, reactive oxygen species, and cell death

Halcrow

Kumar

Hao

et al. 2022

NeuroImmune Pharmacology and Therapeutics

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Objectives Opioids including morphine and DAMGO activate mu-opioid receptors (MOR), increase intracellular reactive oxygen species (ROS) levels, and induce cell death. Ferrous iron (Fe2+) through Fenton-like chemistry increases ROS levels and endolysosomes are “master regulators of iron metabolism” and contain readily-releasable Fe2+ stores. However, mechanisms underlying opioid-induced changes in endolysosome iron homeostasis and downstream-signaling events remain unclear. Methods We used SH-SY5Y neuroblastoma cells, flow cytometry, and confocal microscopy to measure Fe2+ and ROS levels and cell death. Results Morphine and DAMGO de-acidified endolysosomes, decreased endolysosome Fe2+ levels, increased cytosol and mitochondria Fe2+ and ROS levels, depolarized mitochondrial membrane potential, and induced cell death; effects blocked by the nonselective MOR antagonist naloxone and the selective MOR antagonist β-funaltrexamine (β-FNA). Deferoxamine, an endolysosome-iron chelator, inhibited opioid agonist-induced increases in cytosolic and mitochondrial Fe2+ and ROS. Opioid-induced efflux of endolysosome Fe2+ and subsequent Fe2+ accumulation in mitochondria were blocked by the endolysosome-resident two-pore channel inhibitor NED-19 and the mitochondrial permeability transition pore inhibitor TRO. Conclusions Opioid agonist-induced increases in cytosolic and mitochondrial Fe2+ and ROS as well as cell death appear downstream of endolysosome de-acidification and Fe2+ efflux from the endolysosome iron pool that is sufficient to affect other organelles.

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“…Codeine influences the activity of enzymes and works to inhibit metabolic processes such as glycolysis and protein synthesis and antioxidant pathways. Additionally, these modifications reduced body weight to decrease food consumption, leading to a decline in testis weights [41,42]. Fluctuations in androgen levels can lead to modifications in the weight of reproductive organs.…”

Section: Discussionmentioning

confidence: 99%

“…Intervention has been found to result in weight loss [43]. Besides, codeine usage can impact the pituitary gland and induce a decline in the levels of GnRH, FSH, and LH, which in turn inhibits or reduces the production of steroids [42]. Longterm consumption of codeine has been demonstrated to result in testicular degeneration and inhibition of testosterone production [37].…”

Section: Discussionmentioning

confidence: 99%

Effects of Quercetin on Codeine-Induced Reproductive Hormone Disorder

Mohammed,

Osama Adnan,

Abdaulteef Salih

2025

Egyptian Journal of Veterinary Sciences

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T HE CURRENT research studies quercetin's potential to attenuate its effects on adult male rats' codeine-induced reproductive disorders. Twenty-four male adult rats were separated into four sets, consisting of six male adult rats in every set, and a 56-day treatment was obtained. General, the first set is control, and the second set (Q1) obtained quercetin using a gavage needle administered at a specific dosage (300 mg/kg/day). In contrast, the third set (Q2) obtained codeine(50mg/kg/day) using a gavage needle, and the fourth group (Q3) obtained quercetin and codeine until 56 days. As a result of exposure to codeine, the rats› blood concentrations of luteinizing hormone (L.H.) and testosterone (T.) decreased. Nevertheless, the administration of quercetin caused an elevation in the levels of (L.H.) plus (T.) hormones in the set (Q3) compared with the set (Q2). In group (Q2), there were changes in the testicle›s structure and tissue, mainly in the Sertoli cells. In addition, there was amyloid accumulation inside the seminiferous tubules; these cells were disarrangements and lacked germ cells. Meanwhile, rats given quercetin (Q1) showed improvement in testicular histopathological abnormalities. The present study›s findings, taking quercetin with codeine (Q3), demonstrated that quercetin consumption can attenuate the harmful influences of exposure to codeine on male reproductive function. In conclusion, this study investigated quercetin›s capability to protect rat testis from the histological damage that codeine causes by oxidative stress.

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Apoptotic inducement of neuronal cells by codeine: possible role of disrupted redox state and caspase 3 signaling

Cited by 8 publications

References 40 publications

L-Arginine reverses maternal and pre-pubertal codeine exposure-induced sexual dysfunction via upregulation of androgen receptor gene and NO/cGMP signaling

L-Arginine reverses maternal and pre-pubertal codeine exposure-induced sexual dysfunction via upregulation of androgen receptor gene and NO/cGMP signaling

Mu opioid receptor-mediated release of endolysosome iron increases levels of mitochondrial iron, reactive oxygen species, and cell death

Effects of Quercetin on Codeine-Induced Reproductive Hormone Disorder

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