Faculty Bibliography

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

Mucolipidosis IV is a lysosomal storage disease characterized by prominent involvement of the corneal epithelium. A 5-year-old boy with mucolipidosis IV experienced recurrent episodes of severe ocular pain, tearing, and ipsilateral facial flushing. This was suggestive of reflex sympathetic dystrophy, a syndrome of pain and sympathetic hyperactivity. The examination revealed marked corneal surface irregularities, corresponding to massive accumulations of intracytoplasmic storage material in the epithelium. Episodic pain in patients with mucolipidosis IV is an important symptom, presumably reflecting the distinctive corneal ultrastructural abnormality in this disease

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

We have proposed that glutamine serves in a facilitated diffusion process, mediated by the enzyme gamma-glutamyl transferase (gamma-glutamyl transpeptidase; gamma GT) and that it leaves the brain in exchange for entering amino acids. Glutamine is also a precursor of gamma-aminobutyric acid (GABA). Thus, providing an alternate substrate for gamma GT should spare brain glutamine, raise GABA, and cause an anticonvulsant effect. We have found that glycylglycine, the best-known substrate for gamma GT, and delta-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 electroconvulsive 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 gamma GT 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.

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.

Clinical variability in sensory impairment was demonstrated among 75 patients with familial dysautonomia. Older patients had a greater tendency toward increased dysfunction in pain sensation, joint position and Romberg's sign, and vibratory sense. Significant worsening with increased age was supported by retesting of 53 patients after a five-year interval. Sensory and motor axon loss were indicated by electrodiagnostic testing of peripheral nerves and abnormal cortical somatosensory evoked potentials. Familial dysautonomia is a hereditary disease with variable penetrance which involves both failure of intrauterine development of neurons and their postnatal maintenance

Rates of tyrosine and lysine transport and incorporation into protein were measured in control and undernourished weanling rats. Undernutrition was induced by feeding lactating dams a low protein diet (12 percent casein) from birth to day 21. At weaning, body and brain weights of undernourished rats were 50 percent and 88 percent, respectively, of control values. Lysine and tyrosine transport rates into skeletal muscle were reduced by over 75 percent, more than twice the reduction seen in brain. Rates of amino acid incorporation into muscle protein were reduced by approximately 50 percent; the change in rate of incorporation into brain protein was not statistically significant. These data indicate that, in spite of marked retardation of amino acid transport into brain, the brain seems fully capable of maintaining normal rates of protein synthesis.

Two inhibitors of the gamma-glutamyl cycle, methionine sulfoximine (MSO) and 2-imidazolidone-4-carboxylic acid (ICA) were administered to C57LB/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 to 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 gamma-glutamyl cycle in the transport of large neutral amino acids from blood to brain.