PMID- 17805306
OWN - NLM
STAT- MEDLINE
DCOM- 20080902
LR  - 20200319
IS  - 0893-133X (Print)
IS  - 0893-133X (Linking)
VI  - 33
IP  - 8
DP  - 2008 Jul
TI  - Erythropoietin prevents haloperidol treatment-induced neuronal apoptosis through 
      regulation of BDNF.
PG  - 1942-51
AB  - 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.
FAU - Pillai, Anilkumar
AU  - Pillai A
AD  - Department of Psychiatry and Health Behavior, Medical College of Georgia, 
      Augusta, GA 30904, USA. apillai@mail.mcg.edu
FAU - Dhandapani, Krishnan M
AU  - Dhandapani KM
FAU - Pillai, Bindu A
AU  - Pillai BA
FAU - Terry, Alvin V Jr
AU  - Terry AV Jr
FAU - Mahadik, Sahebarao P
AU  - Mahadik SP
LA  - eng
GR  - MH 066233/MH/NIMH NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20070905
PL  - England
TA  - Neuropsychopharmacology
JT  - Neuropsychopharmacology : official publication of the American College of 
      Neuropsychopharmacology
JID - 8904907
RN  - 0 (Antipsychotic Agents)
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (MAP2 protein, rat)
RN  - 0 (Microtubule-Associated Proteins)
RN  - 0 (Recombinant Proteins)
RN  - 0 (bcl-Associated Death Protein)
RN  - 11096-26-7 (Erythropoietin)
RN  - EC 3.4.22.- (Caspase 3)
RN  - J6292F8L3D (Haloperidol)
SB  - IM
MH  - Animals
MH  - Antipsychotic Agents/*antagonists & inhibitors/*pharmacology
MH  - Apoptosis/*drug effects
MH  - Apoptosis Regulatory Proteins/metabolism
MH  - Blotting, Western
MH  - Brain-Derived Neurotrophic Factor/*biosynthesis
MH  - Caspase 3/metabolism
MH  - Cell Death/drug effects
MH  - Cell Survival/drug effects
MH  - Cells, Cultured
MH  - Cerebral Cortex/cytology/drug effects/metabolism
MH  - Erythropoietin/*pharmacology
MH  - Gene Expression Regulation/drug effects
MH  - Haloperidol/*antagonists & inhibitors/*pharmacology
MH  - Immunohistochemistry
MH  - Male
MH  - Mice
MH  - Microtubule-Associated Proteins/metabolism
MH  - Neurons/*drug effects/*metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Recombinant Proteins
MH  - bcl-Associated Death Protein/metabolism
EDAT- 2007/09/07 09:00
MHDA- 2008/09/03 09:00
CRDT- 2007/09/07 09:00
PHST- 2007/09/07 09:00 [pubmed]
PHST- 2008/09/03 09:00 [medline]
PHST- 2007/09/07 09:00 [entrez]
AID - 1301566 [pii]
AID - 10.1038/sj.npp.1301566 [doi]
PST - ppublish
SO  - Neuropsychopharmacology. 2008 Jul;33(8):1942-51. doi: 10.1038/sj.npp.1301566. 
      Epub 2007 Sep 5.