title: Augmentation of glycolytic metabolism by meclizine is indispensable for protection of dorsal root ganglion neurons from hypoxia-induced mitochondrial compromise.
abstract: To meet energy demands, dorsal root ganglion (DRG) neurons harbor high mitochondrial content, which renders them acutely vulnerable to disruptions of energy homeostasis. While neurons typically rely on mitochondrial energy production and have not been associated with metabolic plasticity, new studies reveal that meclizine, a drug, recently linked to modulations of energy metabolism, protects neurons from insults that disrupt energy homeostasis. We show that meclizine rapidly enhances glycolysis in DRG neurons and that glycolytic metabolism is indispensable for meclizine-exerted protection of DRG neurons from hypoxic stress. We report that supplementation of meclizine during hypoxic exposure prevents ATP depletion, preserves NADPH and glutathione stores, curbs reactive oxygen species (ROS) and attenuates mitochondrial clustering in DRG neurites. Using extracellular flux analyzer, we show that in cultured DRG neurons meclizine mitigates hypoxia-induced loss of mitochondrial respiratory capacity. Respiratory capacity is a measure of mitochondrial fitness and cell ability to meet fluctuating energy demands and therefore, a key determinant of cellular fate. While meclizine is an 'old' drug with long record of clinical use, its ability to modulate energy metabolism has been uncovered only recently. Our findings documenting neuroprotection by meclizine in a setting of hypoxic stress reveal previously unappreciated metabolic plasticity of DRG neurons as well as potential for pharmacological harnessing of the newly discovered metabolic plasticity for protection of peripheral nervous system under mitochondria compromising conditions.
authors.affiliation: Department of Surgery, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhuo
authors.affiliation: Department of Surgery, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA.
authors.forename: Murat F
authors.initials: MF
authors.lastname: Gorgun
authors.affiliation: Department of Surgery, University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA. Electronic address: elenglan@utmb.edu.
authors.forename: Ella W
authors.initials: EW
authors.lastname: Englander
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015687:Cell Hypoxia; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects*; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D019344:Lactic Acid / Q000378:metabolism; D008297:Male; D008468:Meclizine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D061251:Primary Cell Culture; D020011:Protective Agents / Q000494:pharmacology*; D013312:Stress, Physiological
chemical_list: D006634:Histamine H1 Antagonists; D020011:Protective Agents; D019344:Lactic Acid; D008468:Meclizine; D000255:Adenosine Triphosphate; D005947:Glucose
keywords: ATP; Dorsal root ganglion neuron; Glutathione; Glycolytic metabolism; Hypoxia; Meclizine; Mitochondrial respiration; Reactive oxygen species