Injury factors and pathological features of toxic milk mice during different disease stages

Abstract

ObjectiveTo evaluate different injury factors and pathological characteristics of the brain at different disease stages in toxic milk (TX) mice, an animal model of Wilson's disease (WD).MethodsThirty TX mice (10 each at 3, 6 and 12 months old) and 30 age‐matched C57 mice were used in this study. Corrected phase (CP) values were determined from susceptibility‐weighted images. Myelin content was determined by measuring inhibition optical density values of Luxol fast blue‐stained sections. Neurofilament protein 68 kDa (NF68), β‐amyloid precursor protein (β‐APP), and myelin basic protein (MBP) levels, as well as copper and iron content, in brain nuclei of the TX mouse were evaluated. Gene amplification ratios for catalase (CAT), GSH peroxidase (GSH‐PX), nitric oxide synthase (NOS), and superoxide dismutase (SOD) in mouse brain were also determined.ResultsCompared with C57 mice, neuronal cell counts were decreased in 12‐months‐old TX mice (p = .011). Myelin content was decreased in the lenticular nucleus (p = .029), thalamus (p = .030), and brainstem (p = .034) of 6‐months‐old TX mice; decreases in the corresponding nuclei (p = .044, .037, and .032, respectively) were also found in 12‐months‐old TX mice. MBP values were lower in the lenticular nucleus and thalamus (p = .027 and .016, respectively) of 6‐months‐old TX mice and in the corresponding nuclei (p = .24 and .040) of 12‐months‐old TX mice. NF‐68 values were lower in the lenticular nucleus and thalamus (p = .034 and .037, respectively) of 6‐months‐old TX mice and in the corresponding nuclei (p = .006 and .012) of 12‐months‐old TX mice. β‐APP values were higher in the thalamus of 6‐months‐old (p = .037) and 12‐months‐old (p = .012) TX mice. Iron content was higher in the lenticular nucleus, thalamus, and cerebellum (p = .044, .038, and .029, respectively) of 6‐months‐old TX mice and in the corresponding nuclei (p = .017, .024, and .029) of 12‐months‐old TX mice. The NOS gene amplification multiple was higher (p = .039), whereas the SOD1 gene amplification multiple was lower (p = .041) in 12‐months‐old TX mice. There was no correlation between metal content or oxidation index and pathological index.ConclusionsThe pathological characteristics of the brains of TX mice may differ at different ages. Different pathogenic factors, including copper and iron deposition and abnormal oxidative stress, are present at different stages.

Symptom aggravation after withdrawal of metal chelating agent therapy in patients with Wilson's disease

“…According to the clinical characteristics of WD patients, WD patients can be divided into hepatic type, cerebral type, and mixed type. According to the characteristics of neurological symptoms, WD patients with cerebral type can be divided into involuntary movements, Parkinson's symptoms, oromandibular dystonia, and mental disorders (Zhou et al, 2019(Zhou et al, , 2020. There are great differences in drug selection and drug (Aggarwal & Bhatt, 2018Fernando et al, 2020;Mulligan & Bronstein, 2020;Zhou et al, 2019Zhou et al, , 2020.…”

Clinical and Genetic Analysis in Neurological Wilson’s Disease Patients With Neurological Worsening Following Chelator Therapy

“…The rapid mobilization of copper during anti-copper therapy and transiently increased amount of toxic free copper in serum and brain were suggested to increase copper-related damage in the brain and lead to neurological worsening ( Brewer et al, 1987 ; Brewer, 1999 ; Stuerenburg, 2000 ; European Association for Study of Liver, 2012 ). Besides, a previous animal study of WD found that the pathological characteristics of the brains of toxic milk mice were different at different stages, that copper deposition at an early stage, copper and iron deposition in the middle stage, and abnormal oxidative stress in the late stage ( Zhou et al, 2019 ). The patients with younger age and shorter time of delayed diagnosis meant that they had a shorter period of copper accumulation and neurological toxicity of copper.…”

Toxic milk mice models of Wilson’s disease

“…Bronson reported that the txJ animals exhibited copper overload in the thalamus and lentiform nucleus even at 3 months of age, but the toxic effect with significant neuronal injury was observed only in the 12-month old population [ 55 ]. In the brain stem and cortex of 12-month-old txJ mice, iron concentration was not elevated and was similar to controls [ 56 ]. Terwel et al described the differences in copper distribution in each of the four brain structures in 12-month-old toxic milk mice.…”

“…Chan et al did not find significant differences in proapoptotic markers suggesting low neuronal apoptotic activity in the neurons of 10-month-old txJ mice, in comparison with the healthy control group [ 60 ]. Magnetic resonance imaging scans showed demyelination in the lenticular nucleus, thalamus, and brainstem of 6- and 12-month-old txJ mice as well as decreased concentrations of myelin basic protein in the thalamus and lenticular nucleus in these animals [ 56 ].…”