Doxycycline could aggravate the absence-like epileptic seizures of WAG/Rij rats via matrix metalloproteinase inhibition

[Display omitted] ► Matrix metalloproteinases (MMPs) are activated in the brain by epileptic seizures. ► MMP-9 activity is also elevated in the genetically absence epileptic WAG/Rij rat. ► Doxycycline increased the epileptic spike-wave-discharges (SWDs) in this rat. ► Broad-spectrum MMP inhibitor GM...

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Bibliographic Details
Published in:Neurochemistry international 2011-10, Vol.59 (5), p.563-566
Main Authors: Kovács, Zsolt, Kékesi, Katalin A., Baracskay, Péter, Juhász, Gábor, Czurkó, András
Format: Article
Language:English
Subjects:
Absence epilepsy
Animals
Biological and medical sciences
Dipeptides - administration & dosage
Dipeptides - pharmacology
Doxycycline
Doxycycline - administration & dosage
Doxycycline - pharmacology
Electrodes, Implanted
Electroencephalography - drug effects
Epilepsy, Absence - chemically induced
Epilepsy, Absence - enzymology
Excitatory Amino Acid Agonists - toxicity
Fundamental and applied biological sciences. Psychology
Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy
Injections, Intraventricular
Kainic Acid - toxicity
Male
Matrix Metalloproteinase Inhibitors
Matrix metalloproteinases
Medical sciences
Nervous system (semeiology, syndromes)
Neurology
Neuronal Plasticity - drug effects
Protease Inhibitors
Rats
Rats, Inbred Strains
Vertebrates: nervous system and sense organs
WAG/Rij rats
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Summary:[Display omitted] ► Matrix metalloproteinases (MMPs) are activated in the brain by epileptic seizures. ► MMP-9 activity is also elevated in the genetically absence epileptic WAG/Rij rat. ► Doxycycline increased the epileptic spike-wave-discharges (SWDs) in this rat. ► Broad-spectrum MMP inhibitor GM6001 (i.c.v.) also increased the SWDs in this rat. ► MMP inhibition could aggravate the absence epileptic activity. Matrix metalloproteinases (MMPs) are known to be activated in the brain by epileptic seizures and elevated MMP-9 activity has been found in a genetic model of generalized absence epilepsy (Wistar Albino Glaxo Rijswijk/WAG/Rij rats). In this study we posed the question, whether MMP inhibitory dose of doxycycline (20mg/kg) could affect the spike-wave-discharges (SWDs) of the WAG/Rij rat. We found that intraperitoneal (i.p.) administration of 20mg/kg doxycycline significantly increased the incidence and duration of SWDs for 4h. As doxycycline has both MMP inhibitory and anti-inflammatory effects we also tested a lower dose of doxycycline (10mg/kg, i.p.) and a selective broad-spectrum MMP inhibitor GM6001 (N-[2(R)-2-(hydroxamido carbonylmethyl)-4-methylpentanoyl]-l-tryptophane methylamide) intracerebroventricularly (i.c.v., 10ng/rat). While 10mg/kg doxycycline significantly increased the SWD number for 1h, GM6001 significantly increased the SWD number during the whole 4-h recording period. Our results could indicate that the induction of MMPs in the epileptic brain, besides contributing to structural remodeling, would also be associated with such functions as homeostatic synaptic plasticity which might counteract epileptic seizures.
ISSN:0197-0186
1872-9754
DOI:10.1016/j.neuint.2011.06.016