1. ¹Department of Psychiatry and Health Behavior, Medical College of Georgia, Augusta, GA, USA
2. ²Medical Research Service Line, Veterans Affairs Medical Center, Augusta, GA, USA
3. ³Department of Neurosurgery, Medical College of Georgia, Augusta, GA, USA
4. ⁴Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA, USA

Correspondence: Dr A Pillai, Department of Psychiatry and Health Behavior, Medical College of Georgia, Medical Research Service (242), Veterans Affairs Medical Center, 5B-103, 1 Freedom Way, Augusta, GA 30904, USA. Tel: +1 706 733 0188 ext. 2491; Fax: +1 706 823 3949; E-mail: apillai@mail.mcg.edu

Received 8 March 2007; Revised 14 July 2007; Accepted 8 August 2007; Published online 5 September 2007.

Abstract

Functional alterations in the neurotrophin, brain-derived neurotrophic factor (BDNF) have recently been implicated in the pathophysiology of schizophrenia. Furthermore, animal studies have indicated that several antipsychotic drugs have time-dependent (and differential) effects on BDNF levels in the brain. For example, our previous studies in rats indicated that chronic treatment with the conventional antipsychotic, haloperidol, was associated with decreases in BDNF (and other neurotrophins) in the brain as well as deficits in cognitive function (an especially important consideration for the therapeutics of schizophrenia). Additional studies indicate that haloperidol has other deleterious effects on the brain (eg increased apoptosis). Despite such limitations, haloperidol remains one of the more commonly prescribed antipsychotic agents worldwide due to its efficacy for the positive symptoms of schizophrenia and its low cost. Interestingly, the hematopoietic hormone, erythropoietin, in its recombinant human form rhEPO has been reported to increase the expression of BDNF in neuronal tissues and to have neuroprotective effects. Such observations provided the impetus for us to investigate in the present study whether co-treatment of rhEPO with haloperidol could sustain the normal levels of BDNF in vivo in rats and in vitro in cortical neuronal cultures and further, whether BDNF could prevent haloperidol-induced apoptosis through the regulation of key apoptotic/antiapoptotic markers. The results indicated that rhEPO prevented the haloperidol-induced reduction in BDNF in both in vivo and in vitro experimental conditions. The sustained levels of BDNF in rats with rhEPO prevented the haloperidol-induced increase in caspase-3 (p<0.05) and decrease in Bcl-xl (p<0.01) protein levels. Similarly, in vitro experiments showed that rhEPO prevented (p<0.001) the haloperidol-induced neuronal cell death as well as the decrease in Bcl-xl levels (p<0.01). These findings may have significant implications for the development of neuroprotective strategies to improve clinical outcomes when antipsychotic drugs are used chronically.