The JNK inhibitor, SP600125, potentiates the glial response and cell death induced by methamphetamine in the mouse striatum

Abstract

This study investigates the effect of the selective Jun NH2-terminal kinase 1/2 (JNK1/2) inhibitor, (SP600125) on the striatal dopamine nerve terminal loss and on the increased interleukin-15 (IL-15) expression and glial response induced by methamphetamine (METH). Mice were given repeated low doses of METH (4 mg/kg, i.p., three times separated by 3 h) and killed 24 h or 7 d after the last dose. SP600125 (30 mg/kg, i.p) was administered 30 min before the last METH injection. Results indicate that METH produced dopaminergic axonal neurotoxicity reflected as a marked decrease in the striatal density of tyrosine hydroxylase-immunoreactive (TH-ir) fibres and dopamine transporter-immunoreactivity (DAT-ir) 24 h after dosing. These effects were not modified by SP600125. This compound also failed to prevent the long-term loss of dopamine levels and DAT observed 7 d following METH injection. Nevertheless, SP600125 potentiated METH-induced striatal cell loss reflected by an increase in Fluoro-Jade immunostaining, cleaved capase-3 immunoreactivity and the number of terminal deoxyncleotidyl transferase-mediated dUTP nick end labelling (TUNEL) positive cells. In line with a deleterious effect of JNK1/2 inhibition, SP600125 increased the astroglial and microglial response induced by METH and interfered with drug-induced IL-15 expression. Together these data indicate that, not only does SP600125 fail to protect against the dopaminergic damage induced by METH but also, in fact, it potentiates the glial response and the non-dopaminergic striatal cell loss caused by the drug.

Cell death caused by the synergistic effects of zinc and dopamine is mediated by a stress sensor gene Gadd45b – implication in the pathogenesis of Parkinson's disease

“…The JNK inhibitor, SP600125, does not protect against the methamphetamine‐induced loss of dopaminergic neurons that has also been associated with JNK activation (Urrutia et al . ).…”

“…In PC12 cells, JNK plays a survival role in prolactin and lowdose ceramide treatment (Wang et al 1999;Cheng et al 2000). The JNK inhibitor, SP600125, does not protect against the methamphetamine-induced loss of dopaminergic neurons that has also been associated with JNK activation (Urrutia et al 2014).…”

SYKT Alleviates Doxorubicin‐Induced Cardiotoxicity via Modulating ROS‐Mediated p53 and MAPK Signal Pathways

“…SB203580 was used as a positive control for SYKT to detect p38 expression level [ 15 ]. SP600125 was used as a positive control for SYKT [ 16 ] to detect JNK expression level. Each assay has 3 repetitions.…”

Fragment C Domain of Tetanus Toxin Mitigates Methamphetamine Neurotoxicity and Its Motor Consequences in Mice

“…with a 3-hour interval between injections as described in detail previously and shown to cause significant striatal toxicity (Granado et al, 2010, 2011a; Ares-Santos et al, 2012, 2014; ElAli et al, 2012; Urrutia et al, 2013, 2014). This regimen is very close to other studies where 4 doses of 5mg/kg at 2-hour intervals were used to induce toxicity (Good et al, 2011; Chiu et al, 2014; Raineri et al, 2015).…”

“…The optical fractionator, Stereoinvestigator program (Microbrightfield Bioscience, Colchester, VT), was used by an experienced observer unaware of treatment conditions as described previously (Ares-Santos et al, 2012; Espadas et al, 2012). The outlines of the striatum and SNpc (including SN pars lateralis) were drawn at low power (2x) using defined anatomic landmarks (Granado et al, 2008a, 2008b; Baquet et al, 2009; Ares-Santos et al, 2012; Urrutia et al, 2014) and the numbers of cells were counted at higher power (100x for the SNpc). To avoid double counting, neurons were counted when their nuclei were optimally visualized, which occurred in only one focal plane.…”