Potential drugs and methods for preventing or delaying the progression of Huntington's disease

Abstract

Huntington's disease (HD) is an autosomal dominant inherited and progressive neurodegenerative disorder with motor dysfunction and cognitive deficits. Although there are no treatments to delay the appearance and the progression of HD, there are potential drugs currently in preclinical and clinical trials that are focused on HD therapy. The signaling pathways involved in HD are not yet clearly elucidated; however, expression of mutant huntingtin protein is considered a key factor in the induction and/or progression of HD. The demonstration that the onset and progression of HD in models of transgenic mice, in particular, are delayed or improved by the application of neurotrophic factors has emphasized their importance in neuroprotection in HD. In addition, other compounds targeting the HD gene or mutant huntingtin protein are currently in preclinical and clinical testing and may show promising neuroprotective effects. There are current patented drugs that are currently being considered as potential therapeutics for HD. These patented drugs may provide promising therapy for HD.

Fig. 1

Model shows the mechanism of release of activity dependent neurotrophic factor (ADNF) and activity dependent neuroprotective protein (ADNP). The release of vasoactive intestinal peptide (VIP) stimulates glial target receptor and induce vesicular excytosis contained ADNF and ADNP. ADNF and ADNP maintain neuronal survival in neurodegenerative diseases through unknown mechanism.

Fig. 2

Molecular and pharmacological mechanism of actions of BDNF in the prevention against the effects of mutant huntingtin protein. First, adenosine 2A receptors play a role in the mechanism of action involving the transactivation of BDNF receptor TrkB. Second, cystamine has a neuroprotective effect that is mediated through the upregulation of chaperone, HSJ1B, and the inhibition of transglutaminase. These proteins are key players in the secretion of clathrin-coated vesicles containing BDNF. Third, ampakines and SSRIs are also suggested to increase the expression or activity of BDNF. Together, these compounds may induce BDNF expression, which leads to neuroprotection. (+) Stimulatory effect; (−) Inhibitory effect.

Fig. 3

Molecular mechanism of actions of GDNF in neuroprotection. GDNF binds to GFRα1/Ret receptor complex and in turn activates the inositol triphosphate (IP3) and the mitogen-activated protein kinase (MAPK) intracellular cascades. MAPK activates Akt, which consequently inactivates caspases 3 and 9 and thus inhibits cell death. Moreover, Akt activates normal huntingtin protein, which in turn maintains cell survival. However, when mutant huntingtin protein is expressed, it may induce downregulation of phosphorylated normal huntingtin protein leading to cell death.