title: Glutamate carboxypeptidase II inhibition behaviorally and physiologically improves pyridoxine-induced neuropathy in rats.
abstract: Pyridoxine is used as a supplement for treating conditions such as vitamin deficiency as well as neurological disorders such as depression, epilepsy and autism. A significant neurologic complication of pyridoxine therapy is peripheral neuropathy thought to be a result of long-term and high dose usage. Although pyridoxine-induced neuropathy is transient and can remit after its withdrawal, the process of complete recovery can be slow. Glutamate carboxypeptidase II (GCP II) inhibition has been shown to improve symptoms of both chemotherapy- and diabetic-induced neuropathy. This study evaluated if GCP II inhibition could behaviorally and physiologically improve pyridoxine-induced neuropathy. In the current study, high doses of pyridoxine (400 mg/kg, twice a day for seven days) were used to induce neuropathy in rats. An orally bioavailable GCP II inhibitor, 2-(3-mercaptopropyl) pentanedioic acid (2-MPPA), was administered daily at a dose of 30 mg/kg starting from the onset of pyridoxine injections. Body weight, motor coordination, heat sensitivity, electromyographical (EMG) parameters and nerve morphological features were monitored. The results show beneficial effects of GCP II inhibition including normalization of hot plate reaction time, foot fault improvements and increased open field distance travelled. H wave frequency, amplitude and latency as well as sensory nerve conduction velocity (SNCV) were also significantly improved by 2-MPPA. Lastly, GCP II inhibition resulted in morphological protection in the spinal cord and sensory fibers in the lumbar region dorsal root ganglia (DRG). In conclusion, inhibition of GCP II may be beneficial against the peripheral sensory neuropathy caused by pyridoxine.
authors.affiliation: Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Michelle C
authors.initials: MC
authors.lastname: Potter
authors.affiliation: Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Krystyna M
authors.initials: KM
authors.lastname: Wozniak
authors.affiliation: Department of Neuropharmacology, Neuro/Sys, Gardanne, France.
authors.forename: Noelle
authors.initials: N
authors.lastname: Callizot
authors.affiliation: Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America; Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Slusher
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D005260:Female; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors*; D005977:Glutarates / Q000494:pharmacology / Q000627:therapeutic use; D009043:Motor Activity / Q000187:drug effects; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000188:drug therapy / Q000503:physiopathology*; D011480:Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011736:Pyridoxine / Q000009:adverse effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012677:Sensation / Q000187:drug effects; D013438:Sulfhydryl Compounds / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C474576:2-(3-mercaptopropyl)pentanedioic acid; D005977:Glutarates; D018696:Neuroprotective Agents; D011480:Protease Inhibitors; D013438:Sulfhydryl Compounds; D043425:Glutamate Carboxypeptidase II; D011736:Pyridoxine