Neonatal epileptic encephalopathy: role of vitamin B-6 vitamers in diagnosis and therapy

The term ‘‘vitamin B-6’’ refers to a group of naturally occurring pyridine derivatives represented by pyridoxine, pyridoxal, and pyridoxamine and their phosphorylated derivatives with similar physiologic actions. These 6 compounds are referred to as vitamin B-6 vitamers. The free forms of the vitamers could be converted to the key coenzymatic form pyridoxal phosphate (PLP) by the action of 2 enzymes, a kinase and an oxidase. Pyridoxal is irreversibly oxidized to 4-pyridoxic acid (PA) by an FAD-dependent aldehyde oxidase in the human liver. PA is excreted in the urine. As such, it is a measure of the total vitamin B-6 metabolized by the body. Phosphorylated pyridoxal and pyridoxamine, the primary animal-derived forms of vitamin B6 vitamers, are converted to the free bases by intestinal alkaline phosphatase and absorbed by a carrier-mediated system. Pyridoxine phosphate (PNP) and pyridoxamine phosphate (PMP) are oxidized by pyridox(am)ine-5#-phosphate oxidase (PNPO) to form PLP. Only free bases can cross the blood-brain barrier. PLP is cleaved by nonspecific membrane-associated alkaline phosphatase to pyridoxal and transported to cerebrospinal fluid (CSF). Uptake of the free vitamers from CSF to brain follows a similar mechanism. The versatility of reactions catalyzed by PLP has been recognized because there are .140 enzymatic reactions catalyzed by PLP-dependent enzymes and these are found in all organisms. They are involved in linking carbon and nitrogen metabolism, replenishing the pool of one-carbon units, and forming biogenic amines (1, 2). The crucial role played by vitamin B-6 in the nervous system is evident from the fact that the putative neurotransmitters dopamine, norepinephrine, serotonin (5-HT), and c-amino butyric acid (GABA) as well as sphingolipids and polyamines are synthesized by PLP-dependent enzymes (3, 4). The concept of the regulatory role of the hypothalamus primarily through neurotransmitters dopamine and 5-HT is generally accepted. Under conditions of vitamin B-6 deficiency, the hypothalamo-pituitiary-end organ systems are affected. Vitamin B-6 status has a significant effect on 5-HT and GABA, neurotransmitters that control pain perception, anxiety, and depression (2). Vitamin B-6 also has a significant role in the cardiovascular system through its role in the metabolism of methionine/homocysteine and more directly through the inhibitory effect of PLP on both major calcium channels, the L-type as well as the ATPmediated channels (2). The role of pyridoxamine as an inhibitor of pathogenic glycation and oxidative damage in preventing agerelated aortic stiffening and vascular resistance places it in the category of a multifunctional pharmaceutical agent (5, 6). The use of PLP in the treatment of autoimmunity and in transplant rejection has been indicated (7). The PLP-dependent enzyme glutamic acid decarboxylase (GAD) decarboxylates the excitatory neurotransmitter glutamate to produce GABA, an inhibitory neurotransmitter. Thus, vitamin B-6 status is a major contributor to the balance between neuronal excitatory and inhibitory states. The induction of congenital vitamin B-6 deficiency in rats was shown to result in pups with spontaneous neonatal convulsions (8). In addition, the effect of vitamin B-6 deficiency during the critical period in the development of the central nervous system in the rat had significant effects on various electrophysiologic variables. The bursts of high-voltage spikes during spontaneous electroencephalographic activity as well as the spontaneous convulsions observed, reflected the decrease in cerebral GABA concentration in the brain of the deficient rats (9). Domoic acid, a rigid structural analog of glutamate, is a neuroexcitant. Acute hippocampal administration of picomole amounts of domoic acid led to electroencephalography epileptiform seizure discharge activity (10, 11). In other experiments, electroencephalography recordings in the cerebral cortex of adult mice given a single subconvulsive dose of domoic acid exhibited typical spike and wave discharges. The administration of sodium valproate, nimodipine, or pyridoxine simultaneously with or after domoic acid administration resulted in significantly less spike and wave activity. Thus, pyridoxine has a significant neuroprotective activity. The inhibitory effect of PLP on calcium transport is also crucial to its neuroprotective action (12). The use of pyridoxine in the treatment of neonatal and infantile epileptic encephalopathy (NEE) has been in vogue for decades