Normal brain homeostasis

Besides the well-established role of cytokines in the immune system, several recent reports demonstrated that chemokines also play a role in the central nervous system (CNS) (B2, Ml3). In the CNS, chemokines are constitutively expressed by microglial cells, astrocytes, and neurons, and their expression can be increased after induction with inflammatory mediators (M13). Chemokines are involved in brain development and in the maintenance of normal brain homeostasis, and play a role in the migration, differentiation, and proliferation of glial and neuronal... 

Two inherited human diseases that represent abnormal copper metabolism are Menkes syndrome and Wilson s disease. Menkes syndrome, with symptoms similar to those of copper deficiency, is characterized by a progressive brain disease, abnormally low copper concentrations in liver and other tissues, and diminished ability to transfer copper across the absorptive cells of the intestinal mucosa (USEPA 1980 Aaseth and Norseth 1986). Wilson s disease (hepatolenticular degeneration) is the only significant example of copper toxicity in humans. Wilson s disease is an autosomal recessive disorder that affects normal copper homeostasis and is characterized by excessive... 

Normal function of the brain depends on the BBB, which provides a highly selective barrier between the blood and the brain parenchyma that creates a special microenvironment crucial for brain homeostasis. Endothelial cells, astrocytes, perivascular microglia, neurons, and pericytes comprise the neurovascular unit (Fig. 1) (Ballabh... 

Genetic and nutritional studies have illustrated the essential nature of copper for normal brain function. Deficiency of copper during the foetal or neonatal period will have adverse effects both on the formation and the maintenance of myelin (Kuo et al., 2001 Lee et al., 2001 Sun et al., 2007 Takeda and Tamana, 2010). In addition, various brain lesions will occur in many brain regions, including the cerebral cortex, olfactory bulb, and corpus striamm. Vascular changes have also been observed. It is also of paramount importance that excessive amounts of copper do not occur in cells, due to redox mediated reactions such that its level within cells must be carefully controlled by regulated transport mechanisms. Copper serves as an essential cofactor for a variety of proteins involved in neurotransmitter synthesis, e.g. dopamine P-hydroxylase, which transforms dopamine to nor-adrenahne, as well as in neuroprotection via the Cu/Zn superoxide dismutase present in the cytosol. Excess free copper is however deleterious for cell metabolism, and therefore intracellular copper concentration is maintained at very low levels, perhaps as low as 10 M. Brain copper homeostasis is still not well understood. 

Patients sustain convulsions and neurological deterioration. The urine contains low levels of the metabolites of serotonin, norepinephrine and dopamine. The reductase also plays a role in the maintenance of tetrahydrofolate levels in brain, and some patients have had low folate levels in the serum and CNS. Treatment has been attempted with tryptophan and carbidopa to improve serotonin homeostasis and with folinic acid to replete diminished stores of reduced folic acid. This therapy is sometimes effective. Diagnosis involves assay of DHPR in skin fibroblasts or amniotic cells. Phenylalanine hydroxylase activity is normal. 

Alterations in brain iron metabolism have been reported, resulting in increased iron accumulation in Huntington s disease. This was particularly the case in basal ganglia from patients with HD compared to normal controls. In studies in embryonic stem cells, huntingtin was found to be iron-regulated, essential for the function of normal nuclear and perinuclear organelles and to be involved in the regulation of iron homeostasis. 

The findings demonstrated that DRD is caused by a partial BH4 deficiency in the brain. In general, disorders caused by an inborn error of metabobsm show recessive inheritance, as half of the enzyme activity is usually sufficient enough to maintain homeostasis in vivo. To the contrary, DRD is a dominant disorder with low penetrance, even though the causative gene for DRD is that for an enzyme, GCH. The marked decrease (to approximately 20% of controls) in the neopterin content in the CSF (cerebrospinal fluid) from DRD patients suggests that GCH activity in the brain of DRD patients is also about 20% of that for normal individuals. Because neopterin is a metabolite of dihy-droneopterin triphosphate, the product of GCH, the neopterin content in the CSF is thought to reflect the GCH activity in the brain. 

---