Limbic seizure and brain damage produced by kainic acid: Mechanisms and relevance to human temporal lobe epilepsy

A current hypothesis links the neuroexcitatory properties of certain acidic amino acids to their ability to cause selective neuronal lesions. Intracerebral injection of the neuroexcitatory tryptophan metabolite, quinolinic acid, has behavioral, neurochemical, and neuropathological consequences reminiscent of those of exogenous excitotoxins, such as kainic and ibotenic acids. Its qualities as a neurotoxic agent suggest that quinolinic acid should be considered as a possible pathogenic factor in neurodegenerative disorders.

https://science.sciencemag.org/content/sci/219/4582/316.full.pdf

Quinolinic acid: an endogenous metabolite that produces axon-sparing lesions in rat brain

Among 141 consecutive patients with neuro-psychiatric abnormalities due to cobalamin deficiency, we found that 40 (28 percent) had no anemia or macrocytosis. The hematocrit was normal in 34, the mean cell volume was normal in 25, and both tests were normal in 19. Characteristic features in such patients included paresthesia, sensory loss, ataxia, dementia, and psychiatric disorders; longstanding neurologic symptoms without anemia; normal white-cell and platelet counts and serum bilirubin and lactate dehydrogenase levels; and markedly elevated serum concentrations of methylmalonic acid and total homocysteine. Serum cobalamin levels were above 150 pmol per liter (200 pg per milliliter) in 2 patients, between 75 and 150 pmol per liter (100 and 200 pg per milliliter) in 16, and below 75 pmol per liter (100 pg per milliliter) in only 22. Except for one patient who died during the first week of treatment, every patient in this group benefited from cobalamin therapy. Responses included improvement in neuropsychiatric abnormalities (39 of 39), improvement (often within the normal range) in one or more hematologic findings (36 of 39), and a decrease of more than 50 percent in levels of serum methylmalonic acid, total homocysteine, or both (31 of 31). We conclude that neuropsychiatric disorders due to cobalamin deficiency occur commonly in the absence of anemia or an elevated mean cell volume and that measurements of serum methylmalonic acid and total homocysteine both before and after treatment are useful in the diagnosis of these patients.

Neuropsychiatric Disorders Caused by Cobalamin Deficiency in the Absence of Anemia or Macrocytosis

Vitamin B12 deficiency causes reversible megaloblastic anemia, demyelinating disease, or both. Current assays have insufficient sensitivity and specificity; methylmalonic acid levels are useful to confirm diagnosis. Parenteral or high-dose oral vitamin B12 is effective therapy.

https://www.nejm.org/doi/pdf/10.1056/NEJMcp1113996

Vitamin B12 Deficiency

Betaine in human nutrition

Children with kwashiorkor showed a high incidence of deranged cellular immunity as evidenced by impairment of delayed cutaneous hypersensitivity reactions to candida and diphtheria toxoid antigens and of lymphocyte transformation after phytohaemagglutinin stimulation. This may contribute to their susceptibility to infection. A correlation was shown between the degree of impairment of tests of cellular immunity and the severity of the kwashiorkor. Once recovery was initiated the skin tests gave the expected positive results and the lymphocyte transformation index improved. Protein deprivation may result in impaired deoxyribonucleic acid (DNA) synthesis and in atrophy of both the thymus and the lymphoid tissue.

Impaired Cellular Immunity in Kwashiorkor with Improvement after Therapy

The mechanism of thrombocytopenia in six patients with falciparum malaria has been studied. All the patients recovered after antimalarial therapy, and cerebral malaria was not a feature. Radioactive-labelled platelets and fibrinogen were injected into the patients during the phase of thrombocytopenia. In all cases recovery of injected platelets was notably subnormal, indicating excessive splenic pooling of platelets. Platelet life span was moderately shortened in all patients, and platelet turnover increased approximately two-fold. Fibrinogen catabolism was moderately increased in all patients, but coagulation tests failed to reveal evidence of disseminated intravascular coagulation. The results suggest that in uncomplicated cases of malaria thrombocytopenia is the result of splenic pooling of platelets aggravated by a moderate decrease in platelet life span. In such cases thrombocytopenia is thus not the result of disseminated intravascular coagulation (D.I.C.), and heparin therapy is not indicated unless there is unequivocal ancillary evidence of D.I.C.

https://www.bmj.com/content/bmj/2/5865/515.full.pdf

Mechanisms of Thrombocytopenia in Malignant Tertian Malaria

Kainic acid, a dicarboxylic acid containing pyrrolidine, is a potent neuronal depolarizing agent in the mammalian central nervous system, being some 50 times more effective than the putative neurotransmitter L-glutamate1–5. As kainic acid is a structural analogue of glutamic acid, it has been proposed that the potent excitatory effects of kainate reflect its restricted conformation, which is optimal for interaction with excitatory glutamate receptors2,4. More recent studies, however, do not support this hypothesis. In invertebrates kainic acid has been found to be a rather weak agonist at excitatory glutamate receptor sites6,7, whereas at the crustacean neuromuscular junction8, on certain neurones of Helix aspersa9 and in the mammalian cerebral cortex3, kainic acid seems to act at receptors distinct from those which mediate the neuroexcitatory action of glutamate. In addition, the ionic requirements for kainate-induced neuronal depolarization differ from those for glutamate-induced depolarization in the mammalian brain10, and glutamate-induced excitation of rat cortical neurones can be antagonized preferentially by drugs which are very weak in blocking kainate-induced depolarization11. Finally, the characteristics of binding sites for 3H-kainic acid in rat brain are consistent with the existence of specific kainate receptors on neuronal membranes12. Thus, the kainate sites may represent receptors for an unidentified endogenous substance probably containing the glutamate structure. Here we report that the pteroylmonoglutamate compound methyltetrahydrofolate (MTHF) is a potent competitor for 3H-kainic acid binding sites in rat cerebellar membranes. This action is specific in that MTHF is very weak or inactive at sites for 3H-glutamate or 3H-γ-aminobutyric acid (GABA) respectively. Electrophysio-logical studies in frog spinal cord suggest that MTHF is an agonist at the kainate receptors. The implications of these results are discussed.

Jack Metz

Papers

Impaired Cellular Immunity in Kwashiorkor with Improvement after Therapy

Mechanisms of Thrombocytopenia in Malignant Tertian Malaria

Methyltetrahydrofolate is a potent and selective agonist for kainic acid receptors

Cobalamin inactivation by nitrous oxide produces severe neurological impairment in fruit bats : protection by methionine and aggravation by folates.

Prevention of folate deficiency by food fortification. II. Absorption of folic acid from fortified staple foods.