Targeting ENT1 and adenosine tone for the treatment of Huntington’s disease

Abstract

Huntington's disease (HD) is caused by an abnormal CAG expansion in the exon 1 of huntingtin gene. The treatment of HD is an unmet medical need. Given the important role of adenosine in modulating brain activity, in this study, levels of adenosine and adenine nucleotides in the cerebral spinal fluid of patients with HD and in the brain of two mouse models of HD (R6/2 and Hdh150Q) were analysed. The expression and activity of ENT1 in the striatum of mice with HD were measured. Targeting adenosine tone for treating HD was examined in R6/2 mice by genetic removal of ENT1 and by giving an ENT1 inhibitor, respectively. The results showed that the adenosine homeostasis is dysregulated in the brain of patients and mice with HD. In patients, the ratio of adenosine/ATP in the cerebral spinal fluid was negatively correlated with the disease duration, and tended to have a positive correlation with independence scale and functional capacity. In comparison to controls, mRNA level of ENT1 was higher in the striatum of R6/2 and Hdh150Q mice. Intrastriatal administration of ENT1 inhibitors increased extracellular level of adenosine in the striatum of R6/2 mice to a much higher level than controls. Chronic inhibition of ENT1 or by genetic removal of ENT1 enhanced the survival of R6/2 mice. Collectively, adenosine homeostasis and ENT1 expression are altered in HD. The inhibition of ENT1 can enhance extracellular adenosine level and be a potential therapeutic approach for treating HD.

The Role of Adenosine Tone and Adenosine Receptors in Huntington's Disease

“…Pharmacological blockade with the low affinity ENT1 inhibitor JMF1907 231 or genetic blockade of ENT (global ENT1 knockout) led to a significant increase in the mean survival time in the R6/2 mouse model of HD. 201 In the same study, there was also an increase in the expression and activity of both ENT1 and ENT2. 201 More support for this hypothesis comes from the fact that there is a decrease in tonic striatal adenosine levels in both R6/2 mice and in the knock-in Hdh(CAG)150 mouse.…”

“…201 In the same study, there was also an increase in the expression and activity of both ENT1 and ENT2. 201 More support for this hypothesis comes from the fact that there is a decrease in tonic striatal adenosine levels in both R6/2 mice and in the knock-in Hdh(CAG)150 mouse. 232 In two genetic animal models, the expression of ectonucleotidases and ADK were also analyzed.…”

“…171 In a more recent study, we found that cerebral spinal fluid (CSF) adenosine levels were significantly lower in HD patients and CSF concentrations of ATP were inversely correlated with the number of CAG repeats. 201 Also, the disease duration of these HD patients was negatively correlated to the adenosine/ ATP ratio. 201 These data suggest that adenosine levels may constitute another biomarker that can be used for diagnosing and treating HD.…”

“…201 Also, the disease duration of these HD patients was negatively correlated to the adenosine/ ATP ratio. 201 These data suggest that adenosine levels may constitute another biomarker that can be used for diagnosing and treating HD. Effective tools to study the neurodegenerative effects seen in HD are chemical-and lesion-induced rodent models.…”

“…232 In two genetic animal models, the expression of ectonucleotidases and ADK were also analyzed. ADK transcript was upregulated only in R6/2 mice, 201 indicating that equilibrative transporters are more likely to represent a key pathogenetic mechanism in HD. This suggests that ENT1 and less selective ENT1/ENT2 inhibitors should be considered as new therapeutic drugs that may decrease the progression of HD.…”