Acute neuroprotection by the synaptic blocker botulinum neurotoxin E in a rat model of focal cerebral ischaemia.
Evidence indicates that accumulation of excitotoxic mediators, such as glutamate, contributes to neuronal damage after an ischaemic insult. It is not clear, however, whether this accumulation is due to excess synaptic release or to impaired uptake. To test a role for synaptic release, here we investigated the neuroprotective potential of the synaptic blocker botulinum neurotoxin E (BoNT/E), that prevents vesicle fusion via the cleavage of the SNARE (soluble NSF-attachment receptor) protein SNAP-25 (synaptosomal-associated protein of 25 kDa). Focal ischaemia was induced in vivo by infusing the potent vasoconstricting peptide endothelin-1 (ET-1) into the CA1 area of the hippocampus in adult rats; BoNT/E or vehicle were administered into the same site 20 min later. Injection of ET-1 was found to produce a transient and massive increase in glutamate release that was potently antagonized by BoNT/E. To assess whether blocking transmitter release translates into neuroprotection, the extent of the ischaemic damage was determined 24 h and 6 weeks after the insult. We found that BoNT/E administration consistently reduced the loss of CA1 pyramidal neurons at 24 h. The neuroprotective effect of BoNT/E, however, was no longer significant at 6 weeks. These data provide evidence that blockade of synaptic transmitter release delays neuronal cell death following focal brain ischaemia, and underline the importance of assessing long-term neuroprotection in experimental stroke studies.
Antonucci
F
F
Istituto di Neuroscienze, Consiglio Nazionale delle Ricerche, via G. Moruzzi 1, 56100 Pisa, Italy.
Cerri
C
C
Maya Vetencourt
J F
JF
Caleo
M
M
D000818:Animals; D001905:Botulinum Toxins / Q000627:therapeutic use*; D002545:Brain Ischemia / Q000139:chemically induced / Q000188:drug therapy*; D056547:CA1 Region, Hippocampal / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D004353:Drug Evaluation, Preclinical; D019332:Endothelin-1 / Q000633:toxicity; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D017551:Microdialysis; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D017966:Pyramidal Cells / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000187:drug effects; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism; D013997:Time Factors
D019332:Endothelin-1; D018696:Neuroprotective Agents; C494210:Snap25 protein, rat; D050825:Synaptosomal-Associated Protein 25; D018698:Glutamic Acid; D001905:Botulinum Toxins; C096326:botulinum toxin type E