Minocycline

Minocycline is a tetracycline analog and can cross the blood–brain barrier (BBB) and inhibits the expression of caspase-3 and caspase-1 [42,43]. Treatment with minocycline proved to be neuroprotective, and to improve the disease phenotype [30,42,44]. A human trial study observed motor (unified HD rating scale (UHDRS)), and cognitive (mini-mental state examination (MMSE)) improvement in 14 HD patients who took 100 mg of minocycline for 6 months [43]. This study was continued for another 18 months, and it was found that MMSE, TMS, total functional capacity (TFC) and independence scale were all stabilized after treatment, reducing the expected decline in these measures. There was also a decrease in psychiatric symptoms at 24 months, which was not apparent after 6 months of treatment [44]. In a pilot study, Thomas et al. found improvement in MMSE, UHDRS, and abnormal involuntary movements scale (AIMS), in 30 patients with HD who were given minocycline for 6 months [45].

#### *3.3. Targeting HTT Aggregation and Clearance*

#### 3.3.1. Congo Red and Trehalose

Congo red dye binds preferably to β-sheets with amyloid fibrils. When injected into HD mice, it preserved normal protein synthesis and degradation, and improved motor functions. This dye promotes clearance of expanded polyQ repeats and inhibits polyglutamine oligomer formation through the disruption of preformed oligomers. Congo red dye also prevented ATP depletion and caspase activation [46–48].

Trehalose disaccharide inhibited the formation of nuclear inclusions, improved altered motor function and was associated with a high rate of survival in R6/2 mice without causing harmful side effects [49–51] (Table 1 and Figure 2).

#### 3.3.2. Compound C2–8

Compound C2–8 inhibits polyglutamine aggregates in brain slices and cell cultures. It has improved motor function, decreased the amount of neuronal atrophy, and decreased the size of the mHTT aggregates in R6/2 mice [52,53]. There is no ongoing human trial using this compound currently listed on clinicaltrials.gov.
