Bone Marrow-Derived Stem Cells Protect against Haloperidol-Induced Brain and Liver Damage in Mice

Abstract

We studied the effect of bone marrow-derived stem cells (BM-SCs) on oxidative stress, inflammation and pathological changes induced in the brain and liver of mice by the antipsychotic drug haloperidol. Mice were intraperitoneally (i.p.) treated with haloperidol at 5 mg/kg for 3 consecutive days followed by i.p. stem cell suspension and euthanized 24h later. Haloperidol resulted in increased brain and liver malondialdehyde (MDA) and nitric oxide contents together with decreased reduced glutathione (GSH). There were also decreased paraoxonase-1 (PON-1) activity in brain and liver and increased interleukin-1β (IL-1 β), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) in brain tissue. Haloperidol produced neuronal necrosis and apoptosis and the appearance of esinophilic areas and strong TNF-α immunoreactivity in the cerebral cortex and striatum of treated mice. In the liver, centrilobular necrosis, inflammatory cell infiltration and sinusoidal haemorrhage were observed. In haloperidol-treated mice, stem cell injection had no significant effects on brain and liver levels of MDA, nitric oxide or GSH. Paraoxonase-1 activity in brain, however, decreased by stem cells application. In brain, there were decreased IL-1β, IL-6 and TNF-α. Brain neurodegenerative changes, brain TNF-immunoreactivity and histological liver damage were all markedly ameliorated after stem cell treatment. These results indicate that stem cells protect against brain and liver toxicity caused by short term haloperidol treatment in high dose. The protective effects of stem cell treatment is likely to result from interfering with cytokine release.