Brain derived neurotrophic factor treatment reduces inflammation and apoptosis in experimental allergic encephalomyelitis.
Multiple sclerosis is an inflammatory disease of the central nervous system (CNS) which includes a neurodegenerative component. Brain derived neurotrophic factor (BDNF) is a neuroprotective agent which might be useful in preventing neurodegeneration but its application has been limited because the blood brain barrier restricts its access to the CNS. We have developed a novel delivery system for BDNF using transformed bone marrow stem cells (BMSC) and undertook studies of EAE to determine whether the delivery of BDNF could reduce inflammation and apoptosis. Mice receiving BDNF producing BMSC had reduced clinical impairment compared to control mice receiving BMSC that did not produce BDNF. Pathological examination of brain and spinal cord showed a reduction in inflammatory infiltrating cells in treated compared to control mice. Apoptosis was reduced in brain and spinal cord based on TUNEL and cleaved Caspase-3 staining. Consistent with the known mechanism of action of BDNF on apoptosis, Bcl-2 and Akt were increased in treated mice. Further studies suggested that these increases could be mediated by inhibition of both caspase dependent and caspase independent pathways. These results suggest that the BDNF delivered by the transformed bone marrow stem cells reduced clinical severity, inflammation and apoptosis in this model.
Makar
Tapas K
TK
VA Maryland Healthcare System, Baltimore, MD 21201, USA.
Trisler
David
D
Sura
Karna T
KT
Sultana
Shireen
S
Patel
Niraj
N
Bever
Christopher T
CT
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism / Q000627:therapeutic use*; D053148:Caspase 3 / Q000378:metabolism; D002452:Cell Count; D015891:Cystatins / Q000235:genetics / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D004852:Epoxy Compounds / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000188:drug therapy* / Q000209:etiology; D051379:Mice; D018991:Myelin Proteolipid Protein; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D015891:Cystatins; D004852:Epoxy Compounds; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; C092940:cathestatin B; C100158:cystatin, egg-white; C435023:myelin proteolipid protein (139-151); D014443:Tyrosine; D051058:Oncogene Protein v-akt; D053148:Caspase 3