Irving Fish

Effect of γ-glutamyl cycle inhibitors on brain amino acid transport and utilization

Two inhibitors of the γ-glutamyl cycle, methionine sulfoximine (MSO) and 2-imidazolidone-4-carboxylic acid (ICA) were administered to C57BL/6J mice. Both agents resulted in a reduced rate of transport of tyrosine from blood to brain and a decreased rate of incorporation of tyrosine from plasma into brain protein. MSO administration also diminished the concentrations of brain tyrosine, dopamine, and norepinephrine. MSO decreased the transport rate of valine by brain as well as the rate of its incorporation into protein when expressed in relation to the plasma specific activity. The results demonstrate a significant role for the γ-glutamyl cycle in the transport of large neutral amino acids from blood to brain.

Use of a Calcium Channel Blocker (Nicardipine HCl) in the Treatment of Childhood Moyamoya Disease

Moyamoya disease is a cerebrovascular disease characterized radiologically by progressive narrowing and occlusion of the arteries contributing to the circle of Willis and its branches. There is formation of an exuberant collateral network of blood vessels at the base of the brain, which is thought to arise in response to chronic ischemia. Clinically, the course is variable, with patients having repeated transient ischemic attacks, strokes, migraine, and seizures. Effective treatment is not available. The etiology and pathophysiology of moyamoya disease are largely unknown. Two patients with arteriographically proven moyamoya disease were identified. Both patients were symptomatic before age 5 years. Despite successful encephaloduroarteriosynangiosis revascularization procedures, they continued to experience an inexorable downhill course. A calcium channel blocker (nicardipine HCl) was introduced in order to prevent further symptoms. After the introduction of nicardipine, no further strokes occurred in either patient. There were no further episodes of transient ischemic attacks, seizures, or headache in one patient and decreased frequency in the other. In patients with moyamoya disease, nicardipine may have a beneficial effect on cerebral hemodynamics and may prevent ischemic sequelae by optimizing existing collateral circulation. (J Child Neurol 1994;9:378-380).

Age related changes in blood-to-brain amino acid transport and incorporation into brain protein

Blood-to-brain amino acid transport consists of at least two components: 1. a fast rate or early process, commonly measured by the intra-carotid bolus injection method and attributed to transport across the capillary endothelium and entry into the astrocytes, and, 2. a slow rate or later component measured over 2 to 15 minutes probably associated with exit from the astrocytes and entry into the neurons. Incorporation into brain protein is temporally related to the second process. In the present study the slow and fast rate transport components and the incorporation into brain protein of tyrosine (Tyr) and Valine (Val) was measured in young adult and aged male C57BL/6 mice. The results indicate that the fast rate transport component is unaffected by age while the rates of the slow process and protein turnover show an exponential decline most marked between 3 and 8 months of age. Changes in the relative incorporation of Tyr and Val suggest that brain protein metabolism is altered qualitatively as well as quantitatively in aging, in these animals.

Anticonvulsant Activity of Glycylglycine and δ-Aminovaleric Acid: Evidence for Glutamine Exchange in Amino Acid Transport

We have proposed that glutamine serves in a facilitated diffusion process, mediated by the enzyme γ‐glutamyl transferase (γ‐glutamyl transpeptidase; γGT) and that it leaves the brain in exchange for entering amino acids. Glutamine is also a precursor of γ‐aminobutyric acid (GABA). Thus, providing an alternate substrate for γGT should spare brain glutamine, raise GABA, and cause an anticonvulsant effect. We have found that glycylglycine, the best‐known substrate for γGT, and δ‐aminovaleric acid (DAVA), a structural analog, have anticonvulsant activity in DBA/2J mice. Both compounds can decrease the incidence and severity of seizures induced by l‐methionine‐rs‐sulfoximine or electroconvul‐sive shock. DAVA was also tested and found to be active against seizures caused by pentylenetetrazol or picrotoxin. [14C]DAVA entered the brain at the rate of 18.7 nmol/g/min. The activity of DAVA as a substrate of γGT was intermediate to that of glycylglycine and glutamine. Preliminary studies have shown that brain glutamine and perhaps GABA are elevated 3 h after administration of DAVA (7.5 mmol/kg). These findings support the theory that glutamine exchange plays a role in amino acid transport across the blood‐brain barrier and suggests a new concept in anticonvulsant therapy. Key Words: Amino acids, transport—γ‐Aminobutyric acid—δ‐Amino valeric acid—Anticonvulsant—Glutamine, exchange—Seizures.

Procedure for measurement of amino acid transport from blood to brain in small animals

Abstract The exponential plasma specific activity curve 2.5 to 12.5 min after injection (sc) of [14C]tyrosine was integrated and divided by time to obtain the mathematical relationship between the average equivalent specific activity S and the measured specific activity S in any individual animal. S is the constant, average value of S that is equivalent to the curvllinearly varying quantity that the body tissues are actually exposed to. Dividing the total brain radioactivity by S gave the tissue Tyr uptake U. The function dU dt is linear from 2.5 to 12.5 min and represents the rate of uptake of the amino acid. Incorporation into protein was similarly measured. Brain uptake of Tyr averaged 7.06, and the apparent protein incorporation was 1.99 nmol/g of brain per min. The γ-glutamyl cycle inhibitor l -methionine-RS-sulfoximine reduced total brain uptake of tyrosine by 42.8% and the apparent rate of protein incorporation by 39.0%.

Amino acid transport inhibition: Brain and behavioral correlates

In vivo inhibition of uptake 14C-L-valine by brain following subcutaneous administration of either of two gamma-glutamyl cycle enzyme inhibitors, 2-imidazolidone-4-carboxylic acid (ICA), or, L-methionine-S-sulfoximine (MSO) is documented in C57BL/6J mice. Dose related decrease in exploratory activity, impairment of memory for foot shock, and reduced operant responding for food reinforcement parallels the time course for interference with uptake of a large neutral amino acid by these two compounds previously shown to inhibit different enzymes in the gamma-glutamyl cycle subserving active amino acid transport.

Baclofen in the Treatment of Polymyoclonus in a Patient With Unverricht-Lundborg Disease

with manifestations sometimes not readily appreciated because of the difficulty of examining a small child or until the disease evolves. Thorough, repeated clinical examination and brain imaging are appropriate. Iqbal N. Allarakhia, MD Department of Pediatrics (Pediatric Neurology) University of Michigan Medical Center Ann Arbor, Michigan Jonathan D. Trobe, MD Departments of Ophthalmology and Neurology WK Kellogg Eye Center University of Michigan Medical Center Ann Arbor, Michigan

Baclofen in the Treatment of Polymyoclonus and Ataxia in a Patient With Homocystinuria

A patient with homocystinuria due to cystathionine β-synthase deficiency developed severe progressive polymyoclonus and ataxia. To our knowledge, this is the first time polymyoclonus and ataxia have been reported in association with homocystinuria. Although cerebrovascular thrombosis is usually thought to be responsible for neurologic dysfunction in homocystinuric patients, no infarctions were demonstrated on magnetic resonance imaging scans in our case. We have previously reported that baclofen dramatically improved the polymyoclonus and ataxia in a patient with Unverricht-Lundborg disease. Baclofen given to our patient reversed the polymyoclonus and the ataxia as well. This suggests that patients with polymyoclonus and ataxia, no matter what the etiology, may benefit from the use of baclofen. (J Child Neurol 1995; 10:294-296).

Pre-natal amino acid transport inhibition: Long term influences on behavior and protein metabolism

DBA/2J mice were exposed in utero, between days 15-18 of gestation, to either of two enzyme inhibitors, previously shown to decrease blood-brain, large-neutral amino acid transport in adults: L-methionine-RS-sulfoximine and 2-imidazolidone-4-carboxylic acid. The young mice demonstrated persistently altered motor behavior relative to saline controls when 40-42 days old and evidence of differences in the entry and incorporation of 14C-valine in brain at up to 80 days of age. The findings suggest that interference with blood-brain amino acid transport in utero has long term consequences. This may be related to some human conditions such as maternal phenylketonuria.

The electroencephalogram in clinical pediatrics.

The electroencephalogram represents an electrical summary of the organizational patterns and the total physical-chemical processes taking place in the brain at the time of the recording. Itis affected by (1) artifacts secondary to head movements, muscle potentials, and eye movements, (2) physiological factors, such as state of consciousness, hyperventilation, and maturity of the brain, (3) metabolic factors such as temperature, thyroid function, electrolyte changes, and numerous other metabolic factors, and (4) drugs. Brain dysfunction also causes changes in the electroencephalogram. The electroencephalogram is useful in some, but not all, types of brain dysfunction. In general, the electroencephalogram is most likely to be abnormal if the underlying disease is acute or ongoing, or if the disease is associated with seizures. Focal lesions may appear when none is suspected clinically. The electroencephalogram can be an invaluable aid in dealing with epilepsy. Petit mal epilepsy cannot be diagnosed without it, and infantile spasms are diagnosed with considerably greater certainty if the electroencephalogram shows hypsarrhythmia. Patients with seizures which appear to be generalized may have an electroencephalogram with focal abnormalities; this may be the only clue that a focal lesion exists. Psychomotor epilepsy is sometimes difficult to differentiate from sociopathic behavior, and the electroencephalogram can be helpful. The electroencephalogram is less useful in chronic static conditions such as mental retardation, minimal cerebral dysfunction, or behavior disorders, unless there is associated epilepsy or ongoing brain pathology. More recently, the electroencephalogram has been used to estimate gestational age with reasonable accuracy. With the aid of a computer, responses to auditory and visual stimuli have been recorded on the electroencephalogram. These techniques, although not in general use at the present time, hold considerable promise for the future. They mark the beginnings of a new dimension in using the electroencephalogram as a tool in helping the clinician evaluate and understand brain development, and in helping him recognize early signs of disease in the developing brain.