Original articleAstrocytic mobilization of glutathione peroxidase-1 contributes to the protective potential against cocaine kindling behaviors in mice via activation of JAK2/STAT3 signaling
Graphical abstract
Introduction
Cocaine has been shown to possess convulsant effects in both rodents [1], [2] and human [3], [4]. The doses required to induce convulsant activity in rodents are quite high [5], [6], [7], and are comparable to doses of cocaine clinically associated with a drug overdose [8]. It is probable that a significant number of the clinical reports of cocaine-induced seizures are the result of the acute administration of high doses of cocaine [9], [10]. Studies indicated that 30% of chronic cocaine users exhibit memory impairments [10], and 7.8% of them experience cocaine-associated seizures [11]. Another retrospective survey documented that 65% of emergency room admissions for illicit drug-induced seizures were associated with cocaine abuse [12]. Furthermore, the repeated and intermittent administration of cocaine potentiated susceptibility to cocaine-induced seizures [5], [13]. This sensitization to the convulsant effects of cocaine has been termed “cocaine kindling” [5], [14] because of its similarities to other pharmacological and electric kindling processes. Previous report showed that reactive oxygen species (ROS) were produced after a single and repetitive administration of cocaine at low doses, indicating that oxidative burdens are involved in cocaine-mediated pharmacological action [15].
Glutathione peroxidase (GPx) is the most important component in the glutathione-mediated antioxidant system. GPx catalyzes the degradation of hydrogen peroxide (H2O2) and other hydroperoxides into water and alcohols, respectively [16]. Since catalase is mainly expressed in the peroxisomes and its activity is very low in the brain [17], GPx is regarded as the major antioxidant enzyme in the brain [18]. A selenium-dependent GPx-1 is the most abundant all of GPx isoforms (from GPx-1 to GPx-8) that have been identified [19].
GSH is a physiological substrate for GPx-1 in coping with ROS [20]. The GSH system is central to lipid peroxide removal [21]. We demonstrated that induction of GSH system is essential for preventing convulsive behaviors [22]. Interestingly, compensative induction of nuclear factor E2-related factor-2 (Nrf-2) gene induced by cocaine was correlated with antioxidant activity, while inhibition of Nrf-2 caused cell death through decreased GSH [23]. Therefore, it is plausible that impaired Nrf-1/GPx-1/GSH-system is important for inducing oxidative burdens elicited by cocaine.
Nuclear factor kappa B (NFκB) is a sensor of oxidative stress. ROS are critical intermediates for various NFκB-activating signals; when activated, NFκB promotes expression of proteins that participate as central regulators of immune, inflammatory, and apoptotic processes [24]. Previous reports indicate that NF-kB signaling might be involved in cocaine-induced memory impairment [25] and behavioral plasticity [26], suggesting that cocaine treatment induces oxidative burdens in the brain.
It is well-known that the signal transducers and activators of transcription 3 (STAT3) plays an important role in regulating gene expression, specifically increasing the expression levels of genes may be critical for cell survival (e.g., Bcl-2, and Bcl-xL), cell proliferation (e.g., c-Myc), cell-cycle progression (e.g., cyclin D1), angiogenesis (e.g., VEGF), and epileptogenesis [27]. Activation of the Janus kinase (JAK)/STAT pathway and specific phosphorylation of STAT3 were observed after the seizures induced by kainate [28].
Evidence has showed that repeated cocaine administration leads to reactive astrocytosis, as labeled by glial fibrillary acidic protein (GFAP) [29], suggesting that astrocytes are involved in the compensative mechanism against cocaine abuse. In addition, Little et al. [30] demonstrated that the number of activated microglia is significantly higher among cocaine users.
Therefore, the present study was designed to elucidate the role of GPx-1 gene in the cocaine-induced kindling (convulsive) behaviors, to investigate whether GPx-1 gene affects NFκB or JAK2/STAT3 signaling, and to investigate glial modulation in the cocaine-induced convulsive behaviors. We propose here that interactive modulation between JAK2/STAT3 signaling and astrocytic modulation of GPx-1 is critical for anticonvulsive/protective potential against cocaine insult.
Section snippets
Animal
All animals were treated in accordance with the National Institutes of Health (NIH) Public Health Service Policy on Humane Care and Use of Laboratory Animals (2015 Edition; grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) and in accordance with the Institute for Laboratory Animal Research (ILAR) Guidelines for the Care and Use of Laboratory Animals (8th Edition; grants.nih.gov/grants/olaw/Guide-for-the-care-and-use-of-laboratory-animals.pdf). Glutathione peroxidase-1
Repeated treatment with cocaine resulted in significant increases in GPx-1 expression
As shown in Fig. 1A of the experimental design, we examined GPx-1 expression 1 h, 6 h, 12 h, 1 d, 3 d, 7 d, and 14 d after the final cocaine administration in the hippocampus of non-TG and GPx-1 TG mice. Treatment with cocaine resulted in an initial increase in GPx-1 expression 1 h post-cocaine (p < 0.05 vs. respective saline). Cocaine-induced increase in GPx-1 expression is the most prominent 1d post-cocaine in non-TG (p < 0.01 vs. respective saline control) and GPx-1 TG (p < 0.01 vs.
Discussion
The investigation of cocaine-kindling behaviors has been suggested for studying the toxicity associated with cocaine abuse. Cocaine-induced kindling profile in this study is comparable to that described by Miller et al. [5]. We propose here that cocaine-induced compensative induction of GPx-1 may be an important defensive mechanism, and that genetic overexpression of GPx-1 protects against cocaine-induced neurotoxic damage, suggesting that GPx-1 gene affords potential protection against cocaine
Acknowledgements
This study was supported by a grant (14182MFDS979) from the Korea Food and Drug Administration, Republic of Korea, and by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT, Republic of Korea (#NRF-2017R1A2B1003346 and #NRF-2016R1A1A1A05005201). Huynh Nhu Mai and Naveen Sharma were supported by the BK21 PLUS program, National Research Foundation of Korea, Republic of Korea. The English in this manuscript has been
Conflict of interest
The authors declare no conflict of interest.
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2021, Food and Chemical ToxicologyCitation Excerpt :Either AG490 or astrocytic inhibition significantly counteracted GPx-1-mediated protective potentials. Therefore, we suggested that astrocytic modulation between GPx-1 and JAK2/STAT3 may be one of the underlying mechanisms for protection against convulsive neurotoxicity induced by cocaine (Mai et al., 2019c) (Fig. 11). Similarly, amphetamine and related drugs also induce seizures (Hanson et al., 1999).
Glutathione peroxidase-1 knockout potentiates behavioral sensitization induced by cocaine in mice via σ-1 receptor-mediated ERK signaling: A comparison with the case of glutathione peroxidase-1 overexpressing transgenic mice
2020, Brain Research BulletinCitation Excerpt :In our recent study (Pham et al., 2019b), the cocaine-induced oxidative burden activated the expression of the σ‐1 receptor, which may be attenuated by the induction of GPx-1. In line with the current results, we also suggest that interactive astrocytic modulation between GPx-1 and JAK2/STAT3 is critical for neuroprotection against the oxidative burden induced by cocaine (Mai et al., 2019d), although the precise role of astrocytic GPx-1 in cocaine-induced behavioral sensitization remains to be further elucidated. Treatment with cocaine resulted in the significant induction of oxidative stress in the brain of rodents, which might be accompanied by alteration of antioxidant enzymatic activities. (
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The first two authors contributed equally to this work.