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.
Highlights
Glutamate carboxypeptidase II (GCP II; known as Nacetylaspartyglutamate (NAAG) peptidase) is a membrane-bound metalloenzyme that cleaves the abundant neuropeptide NAAG to N-acetylaspartate (NAA) and glutamate [1]
The specific GCPII inhibitor used in this current study, 2-(3-mercaptopropyl) pentanedioic acid (2-MPPA), known as GPI5693, is the first orally bioavailable
We report that daily administration of the potent orally available GCP II inhibitor, 2MPPA, protects against loss in both motor and sensory function as well as neurodegeneration induced by pyridoxine
Summary
Glutamate carboxypeptidase II (GCP II; known as Nacetylaspartyglutamate (NAAG) peptidase) is a membrane-bound metalloenzyme that cleaves the abundant neuropeptide NAAG to N-acetylaspartate (NAA) and glutamate [1]. GCP II inhibitors have been shown to increase extracellular NAAG, decrease glutamate and prevent neurotoxicity in several preclinical disease models where excess glutamatergic transmission is presumed pathogenic [4]. These include pain [5,6,7,8], brain ischemia/stroke [1], motoneuron disease [9], brain and spinal cord injury [10,11], peripheral neuropathy [12,13], epilepsy/ seizures [14] and drug abuse [15,16]. In previously published studies 2MPPA, at similar or greater doses to that tested here, have been shown not to cause any effect when given alone to rats or mice [19,20,21,22]
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