Beneficial effects of glatiramer acetate in Huntington’s disease mouse models: Evidence for BDNF-elevating and immunomodulatory mechanisms

Abstract

Huntington’s disease (HD) is a fatal, neurodegenerative movement disorder that has no cure and few treatment options. In these preclinical studies, we tested the effects of chronic treatment of glatiramer acetate (GA; Copaxone®), an FDA-approved drug used as first-line therapy for MS, in two different HD mouse models, and explored potential mechanisms of action of drug efficacy. Groups of CAG140 knock-in and N171-82Q transgenic mice were treated with GA for up to 1 year of age (CAG140 knock-in mice) or 20 weeks (N171-82Q mice). Various behavioral assays were measured over the course of drug treatment whereby GA treatment delayed the onset and reduced the severity of HD behavioral symptoms in both mouse models. The beneficial actions of GA were associated with elevated levels of promoter I- and IV-driven brain-derived neurotrophic factor (Bdnf) expression and reduced levels of cytokines, in particular, interleukins IL4 and IL12, in the brains of HD mice. In addition, the GA-induced effects on BDNF, IL4 and IL12 levels were detected in plasma from drug-treated mice and rats, suggesting utility as a peripheral biomarker of treatment effectiveness. These preclinical studies support the use of GA as a relevant clinical therapy for HD patients.

Evaluation of Biochemical and Epigenetic Measures of Peripheral Brain-Derived Neurotrophic Factor (BDNF) as a Biomarker in Huntington’s Disease Patients

“…A further possibility is that BDNF is released into the saliva by the nerves innervating the salivary glands. This later possibility suggests that salivary BDNF may represent a better surrogate for brain tissue than plasma; a notion supported by previous observations of reduced BDNF protein levels in the brain of HD mouse models and human HD patients (Ferrer et al, 2000;Zuccato et al, 2001;Duan et al, 2003;Zhang et al, 2003;Corey-Bloom et al, 2017). Future studies should address the source of salivary BDNF, not only to understand fundamental mechanisms involved in the transportation of this protein, but also to better define the use of BDNF as a reliable disease biomarker for HD.…”

“…Brain derived neurotrophic factor levels in plasma were measured using a commercially available kit according to our previous studies (Corey-Bloom et al, 2017). BDNF levels in saliva were measured using a sandwich ELISA modified from a protocol optimized for salivary BDNF (Mandel et al, 2011).…”

IDO and Kynurenine Metabolites in Peripheral and CNS Disorders

“…Central microglia are activated and peripheral monocytes of patients with Huntington's disease are hyper-sensitive to immunogenic stimuli (103). A variety of changes in cytokine expression have been reported in the disorder (100, 104) and it is claimed that immunosuppressant treatment can produce significant amelioration of Huntington's disease symptoms and progression (105).…”

“…Would such a drug break the degeneration-inflammation cycle sufficiently to reduce the symptoms of Huntington's disease or, possibly, halt its progression? Highly relevant to these considerations are reports that the treatment of patients with Huntington's disease using an immune-modulating drug such as glatiramer acetate showed significant beneficial effects (105), emphasizing the need to understand the neuro-immune interactions at the heart of the disorder.…”

Associations between Variants in BDNF/BDNFOS Gene and Lumbar Disc Herniation Risk among Han Chinese People

“…BDNF is a crucial factorin the cell cycle, neurite outgrowth, and synaptic plasticity and has been linked to many human brain disorders 34 . Sequence variations in the BDNF gene may lead to variations in gene expression, further to affect the function of the protein.…”