Dystonia and chorea in acquired systemic disorders.

Dystonia and chorea are uncommon accompaniments, but sometimes the presenting features of certain acquired systemic disorders that presumably alter basal ganglia function. Hypoxia-ischaemia may injure the basal ganglia through hypoperfusion of subcortical vascular watershed regions and by altering striatal neurotransmitter systems. Toxins interfere with striatal mitochondrial function, resulting in cellular hypoxia. Infections may affect the basal ganglia by causing vasculitic ischaemia, through the development of antibodies to basal ganglia epitopes, by direct invasion of the basal ganglia by the organism, or through cytotoxins causing neuronal injury. Autoimmune disorders alter striatal function by causing a vasculopathy, by direct reaction of antibodies with basal ganglia epitopes, or by stimulating the generation of a cytotoxic or inflammatory reaction. Endocrine and electrolyte abnormalities influence neurotransmitter balance or affect ion channel function and signalling in the basal ganglia. In general, the production of chorea involves dysfunction of the indirect pathway from the caudate and putamen to the internal globus pallidus, whereas dystonia is generated by dysfunction of the direct pathway. The time of the onset of the movement disorder relative to the primary disease process, and course vary with the age of the patient and the underlying pathology. Treatment of dystonia or chorea associated with a systemic medical disorder must initially consider the systemic disorder.

Forskolin and camptothecin induce a 30 kDa protein associated with melatonin production in Y79 human retinoblastoma cells.

The synthesis of melatonin in Xenopus retinas, chick and quail retinal cell cultures, and Y79 human retinoblastoma cells is stimulated by cAMP through a protein synthesis-dependent mechanism. In Y79 retinoblastoma cells, combined treatment with the RNA synthesis inhibitor camptothecin and agents that elevate cAMP, such as forskolin, causes a synergistic elevation of melatonin. Using two-dimensional gel analysis we have identified a 30 kDa cytosolic protein (p30) whose radiolabeling was consistently increased in parallel with increases in arylalkylamine N-acetyltransferase activity and melatonin production that were induced by forskolin and/or camptothecin. Pulse-chase experiments suggest that the elevation in radiolabeling of p30 is due to increased synthesis. Three candidate proteins found in the mammalian pineal, protein 14-3-3, malate dehydrogenase, and recoverin, do not comigrate with p30.

RNA synthesis inhibitors increase melatonin production in Y79 human retinoblastoma cells.

Y79 human retinoblastoma cells synthesize melatonin in cell culture thus providing a unique preparation for studying the regulation of melatonin biosynthesis in mammalian retinas. We have previously demonstrated that Y79 cells express NAT and HIOMT activity and produce melatonin in a cAMP- and protein synthesis-dependent manner by increasing NAT, and not HIOMT activity, as has been demonstrated in other retinal and pineal melatonin synthesizing systems. We have extended these studies to investigate the role of RNA synthesis in melatonin regulation, and report here that RNA synthesis inhibitors do not suppress melatonin production in Y79 retinoblastoma cells. Rather, at intermediate concentrations, the inhibitors actinomycin D and camptothecin increase melatonin levels. Camptothecin, a topoisomerase I inhibitor, also increased NAT activity and accumulated cAMP levels in a calcium-dependent manner. This effect on cAMP did not appear to occur through phosphodiesterase, and other regulators of retinal melatonin such as melatonin degradation or components of the dopamine system were unaffected. These results are in contrast with the suppression of melatonin synthesis by RNA synthesis inhibitors observed in rat and chick pineal glands and in chick retinas.

N-acetyltransferase and protein synthesis modulate melatonin production by Y79 human retinoblastoma cells.

Melatonin is synthesized by the vertebrate pineal gland in a circadian fashion and is involved in numerous circadian and seasonal processes in the organism. The vertebrate retina also produces melatonin rhythmically to regulate rhythmic physiological processes in the eye. In both organs, melatonin is synthesized from serotonin by the sequential action of the enzymes, N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT), and can be stimulated by increases in cyclic AMP through a mechanism requiring protein synthesis. The regulation of ocular melatonin biosynthesis in mammals and particularly humans, has not been well studied. Recently, we have shown that Y79 human retinoblastoma cells produce melatonin and that cAMP can stimulate melatonin production. Y79 cells, therefore, provide a model system in which to study melatonin synthesis in human tissue. We report that cAMP stimulates NAT, but not HIOMT activity in Y79 cells, and that stimulation of NAT activity is linearly related to melatonin release. In addition, the stimulation of NAT and melatonin requires protein synthesis. The turnover of NAT is rather rapid, with a half-life of about 20 min. These results suggest that the regulation of melatonin in Y79 retinoblastoma cells is similar to that found in the retina and pineal of other vertebrates.

Anti-thymocyte serum delays clearance of poliovirus from the mouse central nervous system.

Antibody is of primary importance for protection from poliovirus-induced paralysis (poliomyelitis) and from other enterovirus infections. However, the components of the immune response involved in the clearance of an established enterovirus infection of the central nervous system (CNS) are not known. To assess the effect of thymus-dependent immune functions on a CNS poliovirus infection, adult BALB/c mice inoculated intracerebrally with the W-2 strain of human poliovirus type 2 (PV2) were treated with anti-thymocyte serum (ATS) and analyzed for clinical disease, virus persistence, antibody responses, and T-cell proliferation (Tprlf). Half (22 of 44) of the ATS-treated mice showed paralysis and death as compared to 27% (17 of 62) of control mice treated with normal rabbit serum. Virus persisted in the brain for 45 days after infection in 43% (13 of 30) of ATS-treated mice as compared to 3% (1 of 30) of controls. Tprlf to PV as well as Tprlf and antibody responses to control antigens were markedly reduced in ATS-treated mice. However, antibody responses to PV in ATS-treated mice were not suppressed, suggesting that PV may be a T-cell-independent antigen. These findings indicate that ATS-suppressible functions contribute to the clearance of PV from the mouse CNS, apparently via a sensitized T-cell mechanism.

Muscle activity pattern regulates postnatal development of acetylcholinesterase molecular forms in normal mice and mice with motor endplate disease.

We have studied the relative contributions of muscle activity and nerve-supplied materials to the regulation of AChE molecular forms during postnatal development of muscles in normal mice and in mice with motor endplate disease (med mice). Onset of this hereditary disease causes a progressive failure of evoked release of ACh from the motor neuron, which prevents contraction in muscles such as biceps and soleus. In these innervated but inactive muscles, one can examine the consequences of inactivity on the distribution of AChE forms. In normal mouse biceps the distribution of AChE forms, as shown by sucrose-gradient analysis, change substantially after birth; the most dramatic alteration is an increase in G4 AChE from 15 to 45% of total AChE during the third postnatal week. AChE profiles in normal or med biceps are indistinguishable until 10-12 d after birth, but the changes in distribution of AChE forms does not occur in med biceps nor in normal biceps denervated 2 weeks after birth. In contrast, the distributions of AChE forms in a predominantly slow muscle, the soleus, are similar in med and normal mice both early (10 d) and late (20 d) in the course of the disease, and the distributions are affected little by denervation. The profiles of AChE forms seen in normal soleus at all times studied resembled those seen in newborn biceps or biceps inactivated by denervation or the med disease. We conclude that neither innervation, age-dependent changes intrinsic to muscle, nor muscle activity is sufficient to induce the changes we seen in AChE forms in biceps. These results support the hypothesis that neonatal, inactive, or tonically active muscles produce an intrinsic pattern of AChE molecular forms, and that a phasic pattern of activity induces a postnatal redistribution of the AChE molecular forms expressed by the muscle.