Meclizine protects cells against serum withdrawal-induced apoptosis in mutant huntingtin expressing striatal neurons. (A and B) Cell viability measured by the ATP levels of mutant (STHdh^Q111/111) and wild-type (STHdh^Q7/7) striatal cells cultured in the presence or the absence of fetal bovine serum (FBS) and co-treatment with 50 µm meclizine for 24 h (n = 3, *P < 0.01). (C) Western blot analysis of protein extract from mutant STHdh^Q111/111 striatal cells at three time points after the removal of serum and exposure to DMSO or 50 µm meclizine. (D) Dose–response curve showing fold change in viability of mutant STHdh^Q111/111 striatal cells in serum-free media upon treatment with different concentrations of meclizine. Viability was determined by the CellTiter-Glo assay and is expressed as fold change relative to DMSO-treated cells. Solid line represents non-linear regression. Data expressed as the mean ± SD (n = 3 per data point).

OXPHOS inhibitors and not anti-histaminergics or anti-muscarinics confer protection against serum withdrawal-induced cell death in striatal neurons. Fold change in viability for drug treatments versus DMSO. Compounds are organized by the pharmacologic target. Serum treatment was used as a positive control. Data expressed as the mean ± SD (n = 3 per drug), *P < 0.01 after the Bonferroni correction.

Meclizine rescue of STHdh^Q111/111 viability is correlated with its inhibition of cellular respiration. The fold change in viability of STHdh^Q111/111 cells and the corresponding decrease in OCR for increasing concentrations (0, 5, 10, 12.5, 25, 37.5 and 50 µm) of meclizine are plotted. Data are expressed as the mean ± SD (n ≥ 3).

Meclizine protects against neuronal dystrophy in a worm model of polyQ toxicity. (A) Dose–response curves for the rescue of tail mechanosensation (Mec) by increasing dose of meclizine in worms expressing 19Q or 128Q repeat containing N-terminal htt proteins. Data expressed as fold change in tail Mec compared with DMSO treatment. Each data point represents the mean ± SE (n = 3, *P < 0.05). (B) Western blot analysis of protein extract from htt-Q128 expressing worms treated with DMSO or 33 µm meclizine. (C) The htt-Q128 aggregate formation was detected by light microscopy following 33 µm meclizine treatments. At least 180 PLM neurons were scored in 90 worms (n = 3). (D) Fluorescent images of the effect of DMSO or 33 µm meclizine on axonal swelling of htt-128Q expressing worms. Scale bars indicate 5 µm. (E) Axonal swelling in PLM neurons of htt-Q128 expressing worms is observed by light microscopy following DMSO or 33 µm meclizine treatments. At least 180 PLM neurons were scored in 90 worms (n = 3, *P < 0.01).

Meclizine rescues photoreceptor loss in a fly model of polyQ toxicity. (A and B) Transgenic human N-548-Htt-Q128 transgene driven in photoreceptors using elav-GAL4 resulted in time-dependent neurodegeneration as assessed by the number of visible rhabdomeres. (A) Flies expressing mutant N-548-Htt-Q128 have normal complement of seven visible light collecting units (rhabdomeres) per ommatidium at day 0 post-eclosion. (B) Number of rhabdomeres at day 10 post-eclosion. (C) Western blot analysis of lysates from elav-GAL > UAS-N-548-Htt-Q128 adult flies that had been fed on either 33 µm meclizine or DMSO for 10 days. (D) Flies were treated with DMSO vehicle or meclizine at 33 µm for 10 days and the average number of rhabdomeres per ommatidium was calculated and is shown as a distribution. Data expressed as the mean ± SD (n = 2, *P < 0.05).