Caffeic Acid Phenethyl Ester Exerts a Neuroprotective Effect on CNS Against Pentylenetetrazol-Induced Seizures in Mice Atilla Ilhan, 1,5 Mustafa Iraz, 2 Ahmet Gurel, 3 Ferah Armutcu, 3 and Omer Akyol 4 (Accepted July 20, 2004) Since overexcitation of excitatory amino acid is an important mechanism in seizure genesis wherein free radicals have recently been suggested to play a critical role, we explored the effects ofcaffeic acid phenethyl ester (CAPE)administration in pentylenetetrazole (PTZ)- induced seizure in mice. CAPE prevents the oxidative damage in brain tissue induced by PTZ, scavenging reactive oxygen species (ROS). Our results demonstrate that CAPE treat- ment which prevents free radical production and ameliorates seizure severity may be useful at least as an adjunctive treatment of seizure disorders. KEY WORDS: Caffeic acid phenethyl ester; seizure; oxidative damage; brain. INTRODUCTION It has been proposed that oxidative stress is a chief factor and a major cause ofneuronaldeath resulting from excessive activation of NMDA recep- tors (1).The mechanisms by which excessive activa- tion of NMDA receptors lead to neuronal degeneration and death involve the increase in free Ca +2 concentration in the postsynaptic neuron (2). Ca +2 binds to calmodulin and activates nitric oxide synthase, increasing theformation of nitric oxide (NO), that contributesto the neurotoxicprocess. Activation of NMDA receptors also leads to increased production ofsuperoxideradical(O2 - ), which has been also proposed to play a role in the excitotoxic process (3, 4). Superoxide and NO react together to produce peroxynitrite ion, a highly reac- tive species capable of generating hydroxyl radicals (5).Peroxynitrite has also been proposed as a medi- ator of glutamate and nitric oxide neurotoxicity (6). The implication ofoxidative stress in a wide range of disordersleads to the investigations to attenuate the progression of neurodegenerative dis- ease by antioxidant treatment (7). Recent data con- cerningthis problem show the efficacyof some substances with antioxidant properties in the ther- apy of convulsivedisordersand give substantial proof to the hypothesis on crucial role of free radi- cals in the pathogenesis of neurotoxic brain dam- age, i.e., epilepsy (8). Pentylenetetrazole (PTZ) is an agent widely used in the assessment of putative antiepileptic drugs and is suggested to induce repetitive firing of nerve fibersand shorten the refractory period (9). PTZ- induced seizures are associated with a variety of behavioral,neurophysiological and neurochemical alterationsin hippocampaland corticalglutamate 1 Inonu University Medical Faculty,Departments of Neurology, Malatya, Turkey. 2 Ionu University MedicalFaculty,Departments of Pharmacol- ogy, Malatya, Turkey. 3 KaraelmasUniversityMedical Faculty, Departmentof Bio- chemistry, Zonguldak, Turkey. 4 Inonu University Medical Faculty,Departments of Biochemis- try, Malatya, Turkey. 5 Address reprint requests to: Atilla Ilhan, Inonu University Med- ical Faculty,Departmentof Neurology,Turgut Ozal Medical Center,44069 Malatya,Turkey. Tel: +90 422 3410660 ext. 4903;Fax: +90 422 341 0728; E-mail: ailhan@inonu.edu.tr 2287 0364-3190/04/1200–2287/0 2004 Springer Science+Business Media, Inc. Neurochemical Research, Vol. 29, No. 12, December 2004 ( 2004), pp. 2287–2292