Overexpression of spermidine/spermine N1-acetyltransferase elevates the threshold to pentylenetetrazol-induced seizure activity in transgenic mice.
Activation of polyamine catabolism in transgenic mice through an overexpression of spermidine/spermine N(1)-acetyltransferase (SSAT) results in a massive overaccumulation of the diamine putrescine in most tissues including brain. Putrescine pool in transgenic animals was strikingly expanded in every six brain regions analyzed at present. Pons (23-fold), cerebellum (37-fold), cerebrum (34-fold), and hippocampus (16-fold) showed the greatest increases in putrescine levels. Moreover, the molar ratio of putrescine to spermidine was increased in the different brain regions of the transgenic animals on an average of nearly 40-fold. Upon an exposure of the animals to pentylenetetrazol (PTZ) infusions, a compound known to induce epilepsy-like seizure activity, the SSAT transgenic mice showed significantly elevated seizure threshold to both clonic and tonic convulsions in comparison with their syngenic littermates. This difference, however, disappeared when the animals were treated with ifenprodil prior to PTZ infusions. The latter compound acts as an antagonist of N-methyl-D-aspartate receptor by binding to the polyamine site of the receptor. Overexpression of SSAT likewise appeared to protect the transgenic animals from PTZ-induced neuron loss in the hippocampus. As putrescine is known to serve as a precursor to gamma-aminobutyric acid (GABA), we carried out (1)H NMR analyses the results of which revealed that the levels of the inhibitory amino acid GABA and its excitatory counterpart glutamate were indistinguishable in syngenic and transgenic animals in all brain regions analyzed. The present results suggest that the frequently observed enhanced accumulation of putrescine in response to brain insults belongs to neuroprotective measures rather than being a cause of the subsequent injury.
Kaasinen
Selma K
SK
A.I. Virtanen Institute for Molecular Sciences, University of Kuopio, P.O. Box 1627, FIN-70211, Kuopio, Finland.
Gröhn
Olli H J
OH
Keinänen
Tuomo A
TA
Alhonen
Leena
L
Jänne
Juhani
J
D000123:Acetyltransferases / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D015317:Biogenic Polyamines / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002452:Cell Count; D003433:Crosses, Genetic; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000235:genetics / Q000502:physiology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D010433:Pentylenetetrazole; D010880:Piperidines / Q000494:pharmacology; D011700:Putrescine / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000235:genetics / Q000503:physiopathology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D015317:Biogenic Polyamines; D018691:Excitatory Amino Acid Antagonists; D018698:Glutamic Acid; D010433:Pentylenetetrazole; D010880:Piperidines; D011700:Putrescine; D005680:gamma-Aminobutyric Acid; D000099228:Diamine N-Acetyltransferase; C010739:ifenprodil