Disease Modifying Potential of Glatiramer Acetate in Huntington's Disease

Abstract

Background: Deficiencies in brain-derived-neurotrophic-factor have been implicated in the pathogenesis of Huntington's disease (HD). Objective: Glatiramer acetate, an FDA-approved drug used for the treatment of multiple sclerosis, has been shown to increase brain-derived-neurotrophic-factor levels in immune cells; hence, we investigated whether it could have similar effects in striatal cells. Methods: Wild-type and HD striatal cells were treated with glatiramer acetate for 48 hrs. HD transgenic and wild-type mice were injected with glatiramer acetate (1.5 to1.7 mg/mouse) for five days. These treatments were followed by protein measurements for brain-derived-neurotrophic-factor. Results: Glatiramer acetate elicited concentration-dependent increases in brain-derived-neurotrophic-factor protein levels in wild-type and HD striatal cells and in striatal tissue from N171-82Q transgenic mice. Glatiramer acetate also improved metabolic activity of HD striatal cells, and significantly reduced the early hyperactivity phenotype exhibited by N171-82Q transgenic mice. Conclusions: These findings suggest that glatiramer acetate may represent a useful therapeutic approach for HD. The excellent safety and tolerability record of this compound makes it an ideal candidate for drug repurposing efforts.

Evaluating Effects of Glatiramer Acetate Treatment on Amyloid Deposition and Tau Phosphorylation in the 3xTg Mouse Model of Alzheimer’s Disease

“…GA has been used for the treatment of relapsing-remitting multiple sclerosis for more than two decades. Over the last decade, its effects have been found to be beneficial in mouse models of disorders with a prominent neuroinflammatory component such as ischemic injury, glaucoma and Huntington's disease (Bakalash et al, 2005;Corey-Bloom et al, 2014;He et al, 2014;Reick et al, 2016;Cruz et al, 2018). In agreement with what has been previously reported in other models of neurodegeneration (Rentsendorj et al, 2018;Doustar et al, 2020), we found that GA improved cognitive performance in 3xTg AD mice.…”

Exploiting microglial and peripheral immune cell crosstalk to treat Alzheimer’s disease

“…Evaluation of serum and CNS of GA-treated mice showed increased levels of the anti-inflammatory cytokine IL-10 and brain-derived neurotrophic factor (BDNF), both of which are produced by activated Th2 cells [147–149]. In addition, not only has GA been effective in decreasing pathology in models of experimental autoimmune encephalomyelitis, but it has also shown benefits in Huntington’s disease models [149, 150]. GA use in amyloidogenic mouse models successfully reduced plaque load; however, the effects of GA on tau pathology remain untested [141–143].…”

Identification of hepta-histidine as a candidate drug for Huntington’s disease by in silico-in vitro- in vivo-integrated screens of chemical libraries

“…K1127 (Kemptide acetate salt) was not employed for the fourth screening because a computer search suggested a possible similarity between Kemptide acetate salt and glatiramer acetate (Copaxone), which had been tested in an HD mouse model (N171-82Q transgenic mice) and has been previously reported to ameliorate the metabolic activity and parameters of motor function, including jumping counts and stereotypic counts 33 . However, a detailed search ruled out a direct relationship between Kemptide acetate salt and these results.…”