Pharmacological evaluation of SN79, a sigma (σ) receptor ligand, against methamphetamine-induced neurotoxicity in vivo
Introduction
High or repeated methamphetamine administration results in hyperthermia, neurotoxicity, and even mortality (Cruickshank and Dyer, 2009). In response to high doses of methamphetamine, cellular neurotoxic cascades are activated due to excessive dopamine and 5-HT release into the cytoplasm and synapse (Baldwin et al., 1993, Kuczenski et al., 1995, Gough et al., 2002). Damage to dopaminergic and serotonergic neurons, which can be measured as reductions in dopamine transporters (DAT), serotonin transporters (SERT), dopamine and 5-HT levels, is observed in several brain regions in human methamphetamine users, as well as in laboratory animals (Krasnova and Cadet, 2009).
Numerous clinical and imaging studies have indicated an association between neurotoxicity and several neuropsychiatric disorders, including psychosis (Scott et al., 2007). Motor and cognitive deficits have also been reported (Hart et al., 2012, Scott et al., 2007), including a recent study showing that long term methamphetamine abuse can increase the risk of Parkinson's disease (Callaghan et al., 2012). Clinical cases of methamphetamine-related fatalities are also rising (Krasnova and Cadet, 2009, Hart et al., 2012), and these lethal effects have been linked to methamphetamine-induced hyperthermia (Bowyer et al., 1994).
Recent evidence has shown that methamphetamine binds to and produces some of its behavioral effects through sigma (σ) receptors, and these proteins can be targeted to mitigate the effects of methamphetamine (Kaushal and Matsumoto, 2011, Nguyen et al., 2005, Robson et al., 2012). In addition to methamphetamine, the psychostimulant cocaine also binds to σ receptors at physiologically relevant concentrations (Robson et al., 2012). With the aim of developing a medication to counteract the harmful effects of psychostimulant abuse, SN79 (6-acetyl-3-(4-(4-(4-florophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one), a putative σ receptor antagonist with druggable properties, including a long half life and good oral bioavailability, was developed (Kaushal et al., 2011a). SN79 interacts with both σ1 and σ2 receptors (Ki 27 and 7 nM, respectively; Kaushal et al., 2011a). It was also shown to attenuate the acute and subchronic effects of cocaine in mice upon intraperitoneal as well as oral administration, making it a viable preclinical drug candidate (Kaushal et al., 2011a).
In the present study, the involvement of σ receptors in methamphetamine-induced toxicity was further evaluated, with an emphasis on hyperthermia, neurotoxicity, and lethality. Modulation of methamphetamine-induced effects was assessed using the well established σ receptor agonist, di-o-tolylguanidine (DTG), and the novel σ receptor putative antagonist SN79. In the first part of the study, it was determined if DTG worsens the effects of methamphetamine. In the second part of the study, it was determined if SN79 attenuates the hyperthermia, neurotoxicity, and lethality caused by methamphetamine. Four well known markers of methamphetamine-induced neurotoxicity were measured: reductions in striatal dopamine and 5-HT levels, as well as decreases in striatal DAT and SERT expression (Krasnova and Cadet, 2009). Striatal tissue was evaluated in the present investigation because it contains the terminals of monoaminergic neurons that are primarily affected by methamphetamine-induced neurotoxicity (Brunswick et al., 1992, Kovachich et al., 1989, Ricaurte et al., 1980, Seiden et al., 1988).
Methamphetamine also causes an elevation in body temperature (Fukumura et al., 1998, Numachi et al., 2007). Earlier studies have shown that hyperthermia potentiates methamphetamine-induced dopamine and 5-HT depletions and exacerbates oxidative stress in the brain (Bowyer et al., 1994, Fukumura et al., 1998, Hirata et al., 1995), whereas hypothermia protects against these effects (Bowyer et al., 1994). Therefore, in the third part of the study, to determine if the neuroprotective effects of SN79 are associated with its ability to decrease the hyperthermic effects of methamphetamine, correlation analysis compared the body temperatures of mice in the various treatment groups with their corresponding striatal dopamine and 5-HT levels.
In addition to establishing an important involvement of σ receptors in the effects of methamphetamine, the ability of SN79 to be clinically developed as a drug candidate against methamphetamine-induced neurotoxicity was also evaluated as a post-treatment following methamphetamine exposure. Previous post-treatment studies have shown σ receptor antagonists to be effective against cocaine-induced lethality (Matsumoto et al., 2001). Therefore, in the fourth part of this study, post-treatment experiments were conducted to evaluate the effectiveness of orally administered SN79 in attenuating methamphetamine-induced striatal dopaminergic neurotoxicity.
Section snippets
Drugs and chemicals
SN79 (6-acetyl-3-(4-(4-(4-florophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one) was synthesized as previously described (Kaushal et al., 2011a) and provided by Dr. Christopher McCurdy (University of Mississippi, University, MS). (+)-Methamphetamine hydrochloride was obtained from Sigma (St. Louis, MO). For i.p. administrations, the drugs were dissolved in sterile saline and administered in a volume of 10 ml/g body weight. For the p.o. administrations, SN79 was dissolved in water and
Effects of methamphetamine and the σ receptor agonist DTG on lethality
Fig. 1A summarizes the survival of the mice following neurotoxic dosing with methamphetamine in the absence and presence of DTG. There was a dose dependent increase in lethality with methamphetamine alone, although the differences were not statistically significant: 0 mg/kg methamphetamine (saline, 0/10 mice died), 5 mg/kg methamphetamine (0/10 mice died, n.s. compared to saline), 10 mg/kg methamphetamine (5/16 mice died, n.s. compared to saline). Since the 5 mg/kg dose of methamphetamine was the
Discussion
The current study demonstrates that pretreatment with SN79 can mitigate methamphetamine-induced lethality, hyperthermia, and striatal neurotoxicity (reductions in dopamine and 5-HT levels and DAT and SERT expression levels in the striatum). When administered as a post-treatment under oral dosing conditions, SN79 elicited partial recovery in striatal dopamine depletions caused by methamphetamine. These data thus suggest that σ receptors can be targeted to reduce the effects of methamphetamine.
In
Role of funding source
Funding for this study was provided by the National Institutes of Health (NIH). The NIH had no further role in the design of the study; in the collection, analysis and interpretation of the data; in writing the report; and in deciding to submit the paper for publication.
Conflict of interest
No conflicts of interest exist.
Acknowledgments
We appreciate the technical assistance of Dr. Ying Huang during some of the studies involving DTG. This study was supported by the National Institutes of Health National Institute on Drug Abuse (Grants DA013978, DA023205).
References (36)
- et al.
Striatal dopamine release in vivo following neurotoxic doses of methamphetamine and effect of the neuroprotective drugs, chlormethiazole and dizocilpine
Br. J. Pharmacol.
(1993) - et al.
Further studies on the role of hyperthermia in methamphetamine neurotoxicity
J. Pharmacol. Exp. Ther.
(1994) - et al.
Effects of high-dose methamphetamine on monoamine uptake sites in rat brain measured by quantitative autoradiography
Synapse
(1992) - et al.
Increased risk of Parkinson's disease in individuals hospitalized with conditions related to the use of methamphetamine or other amphetamine-type drugs
Drug Alcohol Depend.
(2012) - et al.
Time-course of methamphetamine-induced neurotoxicity in rat caudate-putamen after single-dose treatment
Brain Res.
(2000) - et al.
A review of the clinical pharmacology of methamphetamine
Addiction
(2009) - et al.
Interaction between hyperthermia and oxygen radical formation in the 5-hydroxytryptaminergic response to a single methamphetamine administration
J. Pharmacol. Exp. Ther.
(1997) - et al.
A single dose model of methamphetamine-induced neurotoxicity in rats: effects on neostriatal monoamines and glial fibrillary acidic protein
Brain Res.
(1998) - et al.
Comparative effect of substituted amphetamines (PMA, MDMA, and METH) on monoamines in rat caudate: a microdialysis study
Ann. N.Y. Acad. Sci.
(2002) - et al.
Sigma receptors: biology and therapeutic potential
Psychopharmacology
(2004)
Is cognitive functioning impaired in methamphetamine users? A critical review
Neuropsychopharmacology
Methamphetamine-induced serotonin neurotoxicity is mediated by superoxide radicals
Brain Res.
Synthesis and pharmacological evaluation of 6-acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2-(3H)-one (SN79), a cocaine antagonist, in rodents
AAPS J.
CM156, a high affinity sigma ligand, attenuates the stimulant and neurotoxic effects of methamphetamine in mice
Neuropharmacology
AC927, a sigma receptor ligands, blocks methamphetamine-induced release of dopamine and generation of reactive oxygen species in NG108-15 cells
Mol. Pharmacol.
Role of sigma receptors in methamphetamine-induced neurotoxicity
Curr. Neuropharmacol.
Methamphetamine-induced striatal dopamine release, behavior changes and neurotoxicity in BALB/c mice
Int. J. Dev. Neurosci.
Cited by (21)
Neurotoxicity of methamphetamine: Main effects and mechanisms
2021, Experimental NeurologyBenzimidazolone-based selective σ<inf>2</inf> receptor ligands: Synthesis and pharmacological evaluation
2019, European Journal of Medicinal ChemistryCitation Excerpt :Furthermore, we developed 6-acetyl-3-{4-[4-(4-fluorophenyl)piperazin-1-yl]butyl}-2(3H)-benzoxazolone compound 2 (SN79, Fig. 1) which reduced the toxic and stimulant effects of cocaine, and also caused sedation and incoordination with acute treatment [34]. More studies have suggested that pretreatment with compound 2 afforded protection against methamphetamine-induced hyperthermia, and striatal dopaminergic and serotonergic neurotoxicity in mice [35]. Within the frame of our efforts to develop novel selective σ2R ligands [36], we have developed several σ ligands with high affinity for σ2Rs and preference over σ1Rs.
The sigma-1 receptor as a regulator of dopamine neurotransmission: A potential therapeutic target for methamphetamine addiction
2018, Pharmacology and TherapeuticsSigma receptors as potential therapeutic targets for neuroprotection
2014, European Journal of PharmacologyMethamphetamine-induced toxicity: An updated review on issues related to hyperthermia
2014, Pharmacology and Therapeutics