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. 2016 May;203(1):599-609.
doi: 10.1534/genetics.115.184648. Epub 2016 Mar 18.

A Pharmacogenetic Discovery: Cystamine Protects Against Haloperidol-Induced Toxicity and Ischemic Brain Injury

Haili Zhang  1 , Ming Zheng  1 , Manhong Wu  1 , Dan Xu  1 , Toshihiko Nishimura  2 , Yuki Nishimura  1 , Rona Giffard  1 , Xiaoxing Xiong  1 , Li Jun Xu  1 , J David Clark  3 , Peyman Sahbaie  4 , David L Dill  3 , Gary Peltz  5
Affiliations

A Pharmacogenetic Discovery: Cystamine Protects Against Haloperidol-Induced Toxicity and Ischemic Brain Injury

Haili Zhang et al. Genetics. 2016 May.

Abstract

Haloperidol is an effective antipsychotic agent, but it causes Parkinsonian-like extrapyramidal symptoms in the majority of treated subjects. To address this treatment-limiting toxicity, we analyzed a murine genetic model of haloperidol-induced toxicity (HIT). Analysis of a panel of consomic strains indicated that a genetic factor on chromosome 10 had a significant effect on susceptibility to HIT. We analyzed a whole-genome SNP database to identify allelic variants that were uniquely present on chromosome 10 in the strain that was previously shown to exhibit the highest level of susceptibility to HIT. This analysis implicated allelic variation within pantetheinase genes (Vnn1 and Vnn3), which we propose impaired the biosynthesis of cysteamine, could affect susceptibility to HIT. We demonstrate that administration of cystamine, which is rapidly metabolized to cysteamine, could completely prevent HIT in the murine model. Many of the haloperidol-induced gene expression changes in the striatum of the susceptible strain were reversed by cystamine coadministration. Since cystamine administration has previously been shown to have other neuroprotective actions, we investigated whether cystamine administration could have a broader neuroprotective effect. Cystamine administration caused a 23% reduction in infarct volume after experimentally induced cerebral ischemia. Characterization of this novel pharmacogenetic factor for HIT has identified a new approach for preventing the treatment-limiting toxicity of an antipsychotic agent, which could also be used to reduce the extent of brain damage after stroke.

Keywords: haloperidol toxicity; pharmacogenetics.

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Figures

Figure 1
Figure 1
HIT in C57BL/6J, A/J, and 19 chromosome substitution strains. The time (latency) required for a mouse to make a coordinated movement after it is placed on a vertical mesh screen before (day 0) and after treatment with haloperidol (3 mg⋅kg−1⋅day−1 via continuous release from an implanted pellet) for 5 or 10 days is shown. Each bar represents the average ± SEM for three to four mice per strain. Only CSS12 and CSS10 mice (which have A/J alleles for every gene on chromosome 12 or 10, respectively, on an otherwise C57BL/6 background) had significantly increased latencies after both 5 and 10 days of haloperidol treatment. No other CSS mice exhibited a significant increase in latency after treatment day 5; and the small increases in the measured latencies of CSS2 and CSS14 mice after 10 days of haloperidol treatment were not significant (P > 0.05) after correction for the multiple comparisons.
Figure 2
Figure 2
Cystamine coadministration prevents HIT. (A) In the prevention protocol, mice are first treated with cystamine (10 mg⋅kg−1⋅day−1 ip) for 4 days, followed by treatment with haloperidol (10 mg⋅kg−1⋅day−1 ip) and cystamine (10 mg⋅kg−1⋅day−1 ip). A control group of mice received only haloperidol. The haloperidol-induced latency is then measured after ≥2 days of haloperidol treatment in each group of mice. (B and C) Cystamine prevents HIT in A/J (B) and CSS10 (C) mice. The latency measured in C57BL/6 and A/J mice (B), or in CSS10 mice (C), on the indicated day of haloperidol treatment according to the prevention protocol is shown. Each bar represents the average ± SEM for three to four mice per strain, and the dashed horizontal line indicates the average pretreatment latency. Haloperidol increases the latency in A/J and CSS10 mice, but not in C57BL/6, mice. The calculated P-values for comparison of the cystamine-treated A/J (B) or CSS10 mice (C) and control groups are shown for each treatment day.
Figure 3
Figure 3
Cystamine cannot reverse HIT after it has been established. In the reversal protocol, A/J mice are first treated with haloperidol (10 mg⋅kg−1⋅day−1 ip) for 3 days and then with haloperidol (10 mg⋅kg−1⋅day−1 ip) ± cystamine (10 mg⋅kg−1⋅day−1 ip) on days 4–13. The haloperidol-induced latency is then measured on the indicated day in each group. A line connects the measurements made on the same mouse on different treatment days.
Figure 4
Figure 4
Haloperidol-induced gene expression changes that are strain specific and reversed by cystamine treatment. A/J mice were treated with vehicle (n = 3) or cystamine (10 mg⋅kg−1⋅day−1 ip) for 3 days, followed by treatment with haloperidol (10 mg⋅kg−1⋅day−1 ip) in the presence (n = 4) or absence (n = 4) of cystamine (10 mg⋅kg−1⋅day−1 ip) for 4 days. C57BL/6 mice were treated with haloperidol (10 mg⋅kg−1⋅day−1) (n = 4) or vehicle (n = 3) for 4 days. Four hours after the last treatment, striatal tissue was harvested, and the level of Pmch or Fosb mRNA was assessed by RT-PCR analysis. Haloperidol treatment decreases Pmch and increases Fosb mRNA levels by 60-fold (P = 0.04) and 5-fold (P = 0.003), respectively, in A/J mice. Their expression in C57BL/6 mice was not altered by haloperidol treatment, and the haloperidol-induced expression changes in A/J mice were completely (Pmch) (P = 0.57 relative to vehicle-treated group) or partially (Fosb) (P = 0.07 relative to vehicle-treated group) reversed by cystamine coadministration.
Figure 5
Figure 5
The size of an experimentally induced ischemic brain infarct in A/J and CSS10 mice is greater than in C57BL/6J mice. Infarct size was measured 24 hr postdistal MCA occlusion by 2,3,4-triphenytetrazolium (TTC) staining of whole brain sections prepared from C57BL/6J (n = 4), A/J (n = 4), or CSS10 (n = 4) mice. The extent of ischemic brain damage in A/J mice was twofold greater than in C57BL/6J mice (P = 2 × 10−5). The extent of ischemic damage in CSS10 mice was 1.8-fold increased relative to that in C57BL/6 mice (P = 4 × 10−3) and was similar to that observed in A/J mice. The scanned images of TTC-stained whole brain sections for each animal and the measured infarct size (expressed as the percentage of the cortex) are shown. Each bar represents the average (± SEM) of the infarct volume in the percentage of total cortex volume.
Figure 6
Figure 6
Cystamine administration reduces the infarct volume after ischemic injury in A/J, CSS10, and C57BL/6J mice. Male A/J, CSS10, and C57BL/6J mice were treated with cystamine (10 mg⋅kg−1⋅day−1 ip) (n = 5, 4, and 8 mice per group, respectively) or saline (n = 8, 4, and 7 mice per group, respectively) for 5 days. Then, 24 hr after MCA occlusion, whole brains were obtained to assess the infarct size. Each bar represents the average (± SEM) of the infarct size. The infarct size in the control group was significantly reduced by cystamine administration in A/J mice (56.8% vs. 44.0%, P = 0.01), CSS10 mice (50.1% vs. 27.5%, P = 0.02) and C57BL/6J mice (25.4% vs. 16.4%, P = 0.028).
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