Chronic oxycodone induces axonal degeneration in rat brain

Fan, Ruping; Schrott, Lisa M.; Arnold, Thomas C.; Snelling, Stephen; Rao, Meghana; Graham, Derrel D.; Cornelius, Angela; Korneeva, Nadejda L.

doi:10.1186/s12868-018-0417-0

Cited by 37 publications

(51 citation statements)

References 79 publications

(101 reference statements)

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“…4 In addition, the current study may be the first description of elevated CSF-MBP in opiate-related ATL (3 patients) in humans, suggesting myelin damage; notably, CNS MBP is reduced with chronic demyelination in mice chronically exposed to opiates. 33 Hence, CSF-MBP could be a potential marker to support the diagnosis of and evaluate the extent of myelin damage in ATL.…”

Section: Discussionmentioning

confidence: 99%

Acute Toxic Leukoencephalopathy: Etiologies, Imaging Findings, and Outcomes in 101 Patients

Özütemiz¹,

Roshan²,

Kroll

et al. 2019

AJNR Am J Neuroradiol

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BACKGROUND AND PURPOSE:Prior studies regarding acute toxic leukoencephalopathy (ATL) are either small, or preliminary. Our aim was to evaluate etiologies of and differences in imaging severity and outcomes among various etiologies of ATL. MATERIALS AND METHODS:MRIs of patients with suspected ATL over 15 years were retrospectively reviewed; inclusion criteria were: MRI Ͻ3 weeks of presentation with both DWI and FLAIR. These were jointly graded by two neuroradiologists via a previously described score of severity. Clinical outcome was evaluated via both modified Rankin (mRS) and ATL outcome (ATLOS) scores, each being correlated with the DWI and FLAIR scores. Etiologic subgroups of n Ͼ 6 patients were statistically compared. RESULTS:Of 101 included patients, the 4 subgroups of n Ͼ 6 were the following: chemotherapy (n ϭ 35), opiates (n ϭ 19), acute hepatic encephalopathy (n ϭ 14), and immunosuppressants (n ϭ 11). Other causes (n ϭ 22 total) notably included carbon monoxide (n ϭ 3) metronidazole (n ϭ 2), and uremia (n ϭ 1). The mean DWI/FLAIR severity scores were 2.6/2.3, 3.3/3.3, 2.1/2.1 and 2.0/2.5 for chemotherapeutics, opiates, AHE and immunosuppressants, respectively, with significant differences in both imaging severity and outcome (P ϭ .003-.032) among subgroups, particularly immunosuppressant versus chemotherapy-related ATL and immunosuppressants versus opiates (P ϭ .004 -.032) related ATL. DWI and FLAIR severity weakly correlated with outcome ( ϭ 0.289 -.349, P Ͻ .005) but correlated stronger in the chemotherapy ( ϭ 0.460 -.586, P Ͻ .010) and opiate ( ϭ.472-.608, P Ͻ .05) subgroups, which had the worst outcomes. ATL clinically resolved in 36%, with severe outcomes in 23% (coma or death, 9/16 deaths from fludarabine). Notable laboratory results were elevated CSF myelin basic protein levels in 8/9 patients and serum blood urea nitrogen levels in 24/91. CONCLUSIONS:Clinical outcomes of ATL vary on the basis of etiology, being worse in chemotherapeutic-and opiate-related ATL. Uremia may be a predisposing or exacerbating factor. ABBREVIATIONS:AHE ϭ acute hepatic/hyperammonemic encephalopathy; ATL ϭ acute toxic leukoencephalopathy; ATLOS ϭ acute toxic leukoencephalopathy outcome score; CTL ϭ chronic toxic leukoencephalopathy; MBP ϭ myelin basic protein; NAWMϭ normal appearing white matter; PRES ϭ posterior reversible encephalopathy syndrome; PVWM ϭ periventricular white matter Indicates open access to non-subscribers at www.ajnr.org Indicates article with on-line appendix. http://dx.

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Section: Discussionmentioning

confidence: 99%

Acute Toxic Leukoencephalopathy: Etiologies, Imaging Findings, and Outcomes in 101 Patients

Özütemiz¹,

Roshan²,

Kroll

et al. 2019

AJNR Am J Neuroradiol

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“…However, a human study by Seaton et al has shown that oxy is concentrated in the breastmilk and offspring exposed via the breastmilk may receive less than 10% of a typical therapeutic oral infant dose (0.1-0.2 mg/kg) [32][33][34][35][36]. Despite this low dose, infant exposure to oxy via the breastmilk has been associated with central nervous system depression [37], and a number of animal studies have also revealed deficits in behavior and development associated with perinatal opioid exposure [12,[38][39][40]. Additionally, opiates can pass into the placenta and act on fetal opioid receptors [23][24][25].…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies coupled to high-throughput technologies have further provided new insights into the molecular underpinnings associated with chronic oxy dependency. These include alterations in genes associated with the integrated stress response in the brain [41], induction of apoptotic signaling in neurons by promoting demyelination [39], alterations in reward-related genes [42], axon guidance molecules [42], inflammation/immune-related genes [43], neurotransmitter receptor genes [44] as well as expression of synaptic plasticity genes [45], including key sex-specific neuroplasticity-related genes [46]. miRNAs represent a class of noncoding RNAs that critically regulate gene expression by binding to the 3 UTR of target transcripts, thus blocking their translation.…”

Section: Discussionmentioning

confidence: 99%

Brain-Derived Extracellular Vesicle microRNA Signatures Associated with In Utero and Postnatal Oxycodone Exposure

Shahjin

Guda

Schaal

et al. 2019

Cells

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Oxycodone (oxy) is a semi-synthetic opioid commonly used as a pain medication that is also a widely abused prescription drug. While very limited studies have examined the effect of in utero oxy (IUO) exposure on neurodevelopment, a significant gap in knowledge is the effect of IUO compared with postnatal oxy (PNO) exposure on synaptogenesis-a key process in the formation of synapses during brain development-in the exposed offspring. One relatively unexplored form of cell-cell communication associated with brain development in response to IUO and PNO exposure are extracellular vesicles (EVs). EVs are membrane-bound vesicles that serve as carriers of cargo, such as microRNAs (miRNAs). Using RNA-Seq analysis, we identified distinct brain-derived extracellular vesicle (BDEs) miRNA signatures associated with IUO and PNO exposure, including their gene targets, regulating key functional pathways associated with brain development to be more impacted in the IUO offspring. Further treatment of primary 14-day in vitro (DIV) neurons with IUO BDEs caused a significant reduction in spine density compared to treatment with BDEs from PNO and saline groups. In summary, our studies identified for the first time, key BDE miRNA signatures in IUO-and PNO-exposed offspring, which could impact their brain development as well as synaptic function.Cells 2020, 9, 21 2 of 18 lack of studies that have compared the effect of in utero oxy (IUO) and postnatal oxy (PNO) exposure on synaptogenesis-a key process of the formation of synapses during brain development-in the exposed offspring. Synapses are key communication points between neurons, which play a critical role in the regulation of neurotransmission and brain plasticity [6].One relatively unexplored form of cell-cell communication associated with brain development in response to IUO and PNO exposure is extracellular vesicles (EVs) [7][8][9]. These membrane-bound vesicles, comprised of exosomes and microvesicles, originate from the multivesicular bodies and plasma membrane, respectively. Furthermore, these EVs, which carry a repertoire of cargo, including microRNAs (miRNAs), are shown to induce inflammation and subsequent neuronal damage, thus serving as key mediators of pathogenesis in several neurological and neurodegenerative disorders [10,11]. The main objective of this study was to identify differentially expressed BDEs miRNAs using RNA sequencing (RNA-Seq) and evaluate their impact on synaptic architecture during a key stage of brain development.

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“…Ours and other studies have shown that chronic opioid administration is associated with activation of the pro-apoptotic signaling and neuronal degeneration in animal models [5][6][7][8][9]. In our current study, we analyzed carbonyl content in brain and blood/plasma samples from the same animals that have been used to evaluate oxidative and neurodegenerative effect of oxycodone reported in [5,10].…”

Section: Introductionmentioning

confidence: 89%

Carbonyl-protein content increases in brain and blood of female rats after chronic oxycodone treatment

et al. 2020

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Background: Opioids are the most effective drugs commonly prescribed to treat pain. Due to their addictive nature, opioid pain relievers are now second to marijuana, ahead of cocaine with respect to dependence. Ours and other studies suggest potential toxic effects of chronic opioid administration leading to neuronal degeneration. It has been suggested that protein carbonylation may represent a sensitive biomarker of cellular degeneration. To evaluate whether prolonged oxycodone administration is associated with accumulation of protein aggregates that may contribute to neuronal degeneration we measured protein carbonylation levels in brain and also in blood plasma of rats after 30-days of 15 mg/kg daily oxycodone administration. Results: We observed a significant increase in the level of carbonylated proteins in rat brain cortex after 30-days of oxycodone treatment compare to that in water treated animals. Also, oxycodone treated rats demonstrated accumulation of insoluble carbonyl-protein aggregates in blood plasma. Conclusions: Our data suggests that tests detecting insoluble carbonyl-protein aggregates in blood may serve as an inexpensive and minimally invasive method to monitor neuronal degeneration in patients with a history of chronic opioid use. Such methods could be used to detect toxic side effects of other medications and monitor progression of aging and neurodegenerative diseases.

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Chronic oxycodone induces axonal degeneration in rat brain

Cited by 37 publications

References 79 publications

Acute Toxic Leukoencephalopathy: Etiologies, Imaging Findings, and Outcomes in 101 Patients

Acute Toxic Leukoencephalopathy: Etiologies, Imaging Findings, and Outcomes in 101 Patients

Brain-Derived Extracellular Vesicle microRNA Signatures Associated with In Utero and Postnatal Oxycodone Exposure

Carbonyl-protein content increases in brain and blood of female rats after chronic oxycodone treatment

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