Escalating Methamphetamine Regimen Induces Compensatory Mechanisms, Mitochondrial Biogenesis, and GDNF Expression, in Substantia Nigra

Abstract

Methamphetamine (MA) produces long-lasting deficits in dopaminergic neurons in the long-term use via several neurotoxic mechanisms. The effects of MA on mitochondrial biogenesis is less studied currently. So, we evaluated the effects of repeated escalating MA regimen on transcriptional factors involved in mitochondrial biogenesis and glial-derived neurotrophic factor (GDNF) expression in substantia nigra (SN) and striatum of rat. In male Wistar rats, increasing doses of MA (1-14 mg/kg) were administrated twice a day for 14 days. At the 1st, 14th, 28th, and 60th days after MA discontinuation, we measured the PGC1α, TFAM and NRF1 mRNA levels, indicator of mitochondrial biogenesis, and GDNF expression in SN and striatum. Furthermore, we evaluated the glial fibrillary acidic protein (GFAP) and Iba1 mRNA levels, and the levels of tyrosine hydroxylase (TH) and α-synuclein (α-syn) using immunohistochemistry and real-time polymerase chain reaction (PCR). We detected increments in PGC1α and TFAM mRNA levels in SN, but not striatum, and elevations in GDNF levels in SN immediately after MA discontinuation. We also observed increases in GFAP and Iba1 mRNA levels in SN on day 1 and increases in Iba1 mRNA on days 1 and 14 in striatum. Data analysis revealed that the number of TH cells in the SN did not reduce in any time points, though TH mRNA levels was increased on day 1 after MA discontinuation in SN. These data show that repeated escalating MA induces several compensatory mechanisms, such as mitochondrial biogenesis and elevation in GDNF in SN. These mechanisms can reverse MA-induced neuroinflammation and prevent TH-immunoreactivity reduction in nigrostriatal pathway. J. Cell. Biochem. 118: 1369-1378, 2017. © 2016 Wiley Periodicals, Inc.

Prolonged increase in ser31 tyrosine hydroxylase phosphorylation in substantia nigra following cessation of chronic methamphetamine

“…in situ and in vivo e vidence supports that ser31 TH phosphorylation increases TH activity (Salvatore et al, 2001; Salvatore and Pruett, 2012; Shi et al, 2012; Salvatore et al, 2016). One possible mechanism for this increase may be a MA-related increase in GDNF expression in the SN (Valian et al, 2017). Reduced GDNF expression exacerbates aging-related locomotor impairment following MA exposure compared to mice with intact GDNF signaling (Boger et al, 2007).…”

The Main Molecular Mechanisms Underlying Methamphetamine- Induced Neurotoxicity and Implications for Pharmacological Treatment

“…PGC-1α regulates and coordinates the activity of NRF and TFAM to serve as a nutrient-sensing system that increases mitochondrial biogenesis ( Nervina et al, 2006 ). Using a repeated escalating METH regimen in rats, Valian et al (2017) detected an increase in expression of PGC1α and TFAM in the substantia nigra, but not the striatum. However, Beirami et al (2018) revealed a significant decrease in expression of PGC-1α, NRF, and TFAM in the hippocampus of rats with a different repeated METH administration regimen.…”

Increasing methamphetamine doses inhibit glycogen synthase kinase 3β activity by stimulating the insulin signaling pathway in substantia nigra

“…34 Other studies reported upregulation of glial-derived neurotrophic factor and brain-derived neurotrophic factor by MA exposure, which protected the nigrostriatal dopaminergic pathway against the deleterious effects of the toxic psychostimulant. 23,35,36 In previous studies, we demonstrated that escalating MA regimen-induced mitochondrial biogenesis in SN, which act as a component of the endogenous adaptive mechanisms to prevent MA-induced neurotoxicity in the nigrostriatal pathway at behavioral 22 and molecular levels. 23…”

“…23,35,36 In previous studies, we demonstrated that escalating MA regimen-induced mitochondrial biogenesis in SN, which act as a component of the endogenous adaptive mechanisms to prevent MA-induced neurotoxicity in the nigrostriatal pathway at behavioral 22 and molecular levels. 23…”

“…We previously showed that although repeated administration of increasing doses of MA over 14 days does not impair motor behavior, 22 it induces compensatory mechanisms including increased mitochondrial biogenesis and glial-derived neurotrophic factor expression in substantia nigra (SN). 23 In the current study, we evaluated the gene expression of IR, IRS1, and IRS2, and protein levels of PI3K, phospho-PI3K, Akt, phospho-Akt, GSK3β, and phospho-GSK3β in SN and striatum of rats that received same regimen of repeated MA, immediately after and over a long period of drug discontinuation.…”