Biochemical Study on the Critical Period for Treatment of the Mottled Brindled Mouse

Abstract

Hemizygous mottled brindled mice (Mobr/y mice) were treated by subcutaneous injection of copper and were decapitated on postnatal day 14. Cytochrome c oxidase (COX) activity of the brain mitochondria in the mice given 10 micrograms of copper/g on day 4 or 7 showed significant increases compared with that of untreated Mobr/y animals, and these mice had no neurological symptoms. Mice given 10 micrograms of copper/g on day 12 showed neither increases in COX activity nor clinical improvement. The brain levels of copper, noradrenaline, and dopamine in the mice treated on day 12 were the same as those in animals treated on day 4 or 7. The in vitro activities of dopamine-beta-hydroxylase of the brain were also the same among the treated mice, irrespective of the date of treatment. The results indicate that delays in copper treatment produce irreversible changes in COX activity of the brain and lead to clinical unresponsiveness to treatment.

Prolonged copper depletion induces expression of antioxidants and triggers apoptosis in SH-SY5Y neuroblastoma cells

“…The recovery of Cu,Zn-SOD activity after addition of CuSO 4 to Trien-treated cells, together with Cytox rescue, improved cell viability, indicating that impairment of copper-dependent enzymes is a causal factor in the induction of cell death. Indeed, copper supplementation by injection prevents the neurological disturbances present in the Mottled/Brindled mouse [54]. Bcl-2 levels also revert to control ones; the different response of Mn-SOD is probably due to a different turnover of this protein or to an additional specific effect of Trien.…”

The Female Brindled Mouse as a Model of Menkes' Disease: The Relationship of Fur Pattern to Behavioral and Neurochemical Abnormalities

“…Fujii et al [11] have recently demonstrated that in creases in the activity of the copper-dependent mitochon drial enzyme, cytochrome c oxidase, are associated with improvement of the neurological symptoms of the mice. Based upon these data, they have argued that cyto chrome c oxidase deficiency is the mechanism whereby neuronal damage occurs.…”

“…These injections attenuate the neuronal degener ation of the cerebrum, and make the neuronal mitochon drial changes far less conspicuous [10]. More recently, Fujii et al [11] demonstrated that increases in the activity of the copper-dependent, mitochondrial enzyme cy tochrome c oxidase, specifically, are associated with im provement of the neurological symptoms of the mice, as indicated by fur color, body weight, brain weight and ataxia. They also demonstrated that increases in cy tochrome c oxidase activity occur only if copper treat ment is given before day 12.…”

Menkes disease

“…[47][48][49][50] When Mo br is treated with copper injections within the first week of postnatal period the mice survive and do not develop neurological symptoms. 51 Furthermore, transgenic expression of human ATP7A in Mo br could correct the phenotype even though copper defect was not completely corrected. 52 The mottled blotchy (Mo blo ) phenotype resembles OHS by showing predominantly connective tissue manifestations.…”