Ht. Liu et al., Resistance to excitotoxin-induced seizures and neuronal death in mice lacking the preprotachykinin A gene, P NAS US, 96(21), 1999, pp. 12096-12101
Citations number
41
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Epileptic seizures are associated with increases in hippocampal excitabilit
y, but the mechanisms that render the hippocampus hyperexcitable chronicall
y (in epilepsy) or acutely (in status epilepticus) are poorly understood. R
ecent evidence suggests that substance P (SP), a peptide that has been impl
icated in cardiovascular function, inflammatory responses, and nociception,
also contributes to hippocampal excitability and status epilepticus, in pa
rt by enhancing glutamate release. Here we report that mice with disruption
of the preprotachykinin A gene, which encodes SP and neurokinin A, are res
istant to kainate excitoxicity. The mice show a reduction in the duration a
nd severity of seizures induced by kainate or pentylenetetrazole, and both
necrosis and apoptosis of hippocampal neurons are prevented. Although kaina
te induced the expression of bar and caspase 3 in the hippocampus of wild-t
ype mice, these critical intracellular mediators of cell death pathways wer
e not altered by kainate injection in the mutant mice. These results indica
te that the reduction of seizure activity and the neuroprotection observed
in preprotachykinin A null mice are caused by the extinction of a SP/neurok
inin A-mediated signaling pathway that is activated by seizures. They sugge
st that these neurokinins are critical to the control of hippocampal excita
bility, hippocampal seizures, and hippocampal vulnerability.