Anti-porin antibodies prevent excitotoxic and ischemic damage to brain tissue.
The mitochondrial permeability transition (MPT) is a converging event for different molecular routes leading to cellular death after excitotoxic/oxidative stress, and is considered to represent the opening of a pore in the mitochondrial membrane. There is evidence that the outer mitochondrial membrane protein porin is involved in the MPT and apoptosis. We present here a proof-of-principle study to address the hypothesis that anti-porin antibodies can prevent excitotoxic/ischemia-induced cell death. We generated anti-porin antibodies and show that the F(ab)(2) fragments penetrate living cells, reduce Ca(2+)-induced mitochondrial swelling as other MPT blockers do, and decrease neuronal death in dissociated and organotypic brain slice cultures exposed to excitotoxic and ischemic episodes. These observations present direct evidence that anti-porin antibody fragments prevent cell damage in brain tissue, that porin is a crucial protein involved in mitochondrial and cell dysfunction, and that it is conceivable that antibodies can be used as therapeutic agents.
Perez Velazquez
Jose L
JL
The Hospital for Sick Children, Brain and Behaviour Programme, Department of Paediatrics, University of Toronto, Toronto, Canada. jlpv@sickkids.ca
Kokarovtseva
Larisa
L
Weisspapir
Michael
M
Frantseva
Marina V
MV
D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D002545:Brain Ischemia / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D004285:Dogs; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D008297:Male; D016202:N-Methylaspartate / Q000633:toxicity; D009924:Organ Culture Techniques; D018272:Porins / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D050994:Voltage-Dependent Anion Channels
D000906:Antibodies; D018690:Excitatory Amino Acid Agonists; D018272:Porins; D050994:Voltage-Dependent Anion Channels; D016202:N-Methylaspartate