Central administration of a caspase inhibitor impairs shuttle-box performance in rats.
Recent studies suggest that caspase-3-mediated mechanisms are essential for neuronal plasticity. N-benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val- Asp(OMe)-fluoromethyl ketone (z-DEVD-fmk), a caspase inhibitor with predominant specificity toward caspase-3, has been shown to block long-term potentiation in hippocampal slices. Intrahippocampal infusion of a caspase-3 inhibitor to rats has been shown to significantly impair spatial memory in the water maze. The present work was designed to study whether i.c.v. administration of a caspase-3 inhibitor z-DEVD-fmk impairs learning in other tasks related to specific forms of memory in rats. The rats received bilateral injections of z-DEVD-fmk or N-benzyloxycarbonyl-Phe-Ala-fluoromethyl ketone (z-FA-fmk) ("control" peptide) at a dose of 3 nmol. Administration of z-DEVD-fmk significantly decreased the number of avoidance reactions in some blocks of trials in the active avoidance (shuttle box) learning, while z-FA-fmk had no effect as compared with intact rats. However, only a slight effect of the caspase inhibitor across the session was found. z-DEVD-fmk impaired development of some essential components of the two-way active avoidance performance, such as escape reaction, conditioned fear reaction, and inter-trial crossings. Measurement of caspase-3 activity in rat brain regions involved in active avoidance learning revealed most expressed z-DEVD-fmk-related inhibition of the enzyme activity (about 30%) in the fronto-parietal cortex. A similar effect was close to significant in the hippocampus, but not in the other cerebral structures studied. In primary cultures of cerebellar neurons z-DEVD-fmk (2-50 microM) inhibited caspase-3 activity by 60-87%. We suggest that moderate inhibition of caspase-3 resulting from the central administration of z-DEVD-fmk to rats may impair active avoidance learning. Taking into account previous data on the involvement of neuronal caspase-3 in neuroplasticity phenomena we assume that the enzyme may be important for selected forms of learning.
Stepanichev
M Yu
MY
Department of Functional Biochemistry of the Nervous System, Institute of Higher Nervous Activity and Neurophysiology, Russian Academy of Sciences, Butlerov Street 5A, Moscow 117485, Russia.
Kudryashova
I V
IV
Yakovlev
A A
AA
Onufriev
M V
MV
Khaspekov
L G
LG
Lyzhin
A A
AA
Lazareva
N A
NA
Gulyaeva
N V
NV
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D053148:Caspase 3; D061945:Caspase Inhibitors; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000201:enzymology; D003216:Conditioning, Operant / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D007276:Injections, Intraventricular; D007858:Learning / Q000187:drug effects; D008297:Male; D008568:Memory / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology; D010447:Peptide Hydrolases / Q000737:chemistry / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D011480:Protease Inhibitors; C110772:benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone; D010447:Peptide Hydrolases; C505410:Casp3 protein, rat; D053148:Caspase 3