title: Methamphetamine inhibits the glucose uptake by human neurons and astrocytes: stabilization by acetyl-L-carnitine.
abstract: Methamphetamine (METH), an addictive psycho-stimulant drug exerts euphoric effects on users and abusers. It is also known to cause cognitive impairment and neurotoxicity. Here, we hypothesized that METH exposure impairs the glucose uptake and metabolism in human neurons and astrocytes. Deprivation of glucose is expected to cause neurotoxicity and neuronal degeneration due to depletion of energy. We found that METH exposure inhibited the glucose uptake by neurons and astrocytes, in which neurons were more sensitive to METH than astrocytes in primary culture. Adaptability of these cells to fatty acid oxidation as an alternative source of energy during glucose limitation appeared to regulate this differential sensitivity. Decrease in neuronal glucose uptake by METH was associated with reduction of glucose transporter protein-3 (GLUT3). Surprisingly, METH exposure showed biphasic effects on astrocytic glucose uptake, in which 20 µM increased the uptake while 200 µM inhibited glucose uptake. Dual effects of METH on glucose uptake were paralleled to changes in the expression of astrocytic glucose transporter protein-1 (GLUT1). The adaptive nature of astrocyte to mitochondrial β-oxidation of fatty acid appeared to contribute the survival of astrocytes during METH-induced glucose deprivation. This differential adaptive nature of neurons and astrocytes also governed the differential sensitivity to the toxicity of METH in these brain cells. The effect of acetyl-L-carnitine for enhanced production of ATP from fatty oxidation in glucose-free culture condition validated the adaptive nature of neurons and astrocytes. These findings suggest that deprivation of glucose-derived energy may contribute to neurotoxicity of METH abusers.
authors.affiliation: Laboratory of Neurovascular Oxidative Injury, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: P M Abdul
authors.initials: PMA
authors.lastname: Muneer
authors.forename: Saleena
authors.initials: S
authors.lastname: Alikunju
authors.forename: Adam M
authors.initials: AM
authors.lastname: Szlachetka
authors.forename: James
authors.initials: J
authors.lastname: Haorah
mesh_terms: D000108:Acetylcarnitine / Q000378:metabolism*; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D015153:Blotting, Western; D004734:Energy Metabolism; D005947:Glucose / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008694:Methamphetamine / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism
chemical_list: D008694:Methamphetamine; D000108:Acetylcarnitine; D005947:Glucose