Zonisamide Reduces the Increase in 8‐Hydroxy‐2′‐Deoxyguanosine Levels Formed During Iron‐Induced Epileptogenesis in the Brains of Rats

Abstract

Summary:Purpose: To examine the change of 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels, which are used as a marker for oxidative DNA damage, in iron-induced epileptogenic foci of the rat cerebrum. Method: Male Wistar rats were given a cortical injection of ferric chloride, and their 8-OHdG levels were determined over time. Additional animals were pretreated with the antiepileptic drug zonisamide (ZNS) before the ferric chloride injection, and their 8-OHdG levels were compared with the nonpretreated rats. Results: Fifteen minutes after ferric chloride solution injection, the level of 8-OHdG increased, reaching a maximum 30 minutes after injection. Sixty minutes after injection, the levels coincided with those of controls. ZNS. in concentrations of 50 and 100 mg/kg body weight, prevented the increase of 8-OHdG levels within the cerebrum 30 minutes after iron solution injection. Conclusions:These results indicate that the formation of ironinduced epileptogenic foci in rats is related to DNA-damageinduced reactive oxygen species and that the inhibition of 8-OHdG formation by ZNS after iron injection may be due to the drug's antioxidant activity. The data suggest that free radical species known to be formed during iron salts-induced focal epileptogenesis cause damage to isocortical DNA. Furthermore, ZNS appears to inhibit the focal injuring response to DNA that occurs following iron salts-induced acute epileptogenesis.

Neuronal plasticity: implications in epilepsy progression and management

“…It also reduces voltagedependent T-type Ca 21 currents, modulating GABAmediated inhibition [McAuley et al, 2002]. Its suggested mode of neuroprotection involves a decreased secretion of excitatory amino acids and reduction in post anoxic depolarization as well as free radical scavenging [Komatsu et al, 2000]. ZNS is a weak carbonic anhydrase inhibitor, but this is probably not a significant component of its anticonvulsant action [McAuley et al, 2002].…”

Different Mechanisms Underlying the Antiepileptic and Antiparkinsonian Effects of Zonisamide

“…ZNS protects neurons against free-radical damage by scavenging the hydroxyl and nitric oxide radicals and such action is dose-dependent (Leppik, 2004;Mori et al, 1998;Noda et al, 1999). Especially, ZNS provides scavenging effects against cytosolic and plasma membrane-targeting free radicals in epileptogenic foci (Komatsu et al, 2000;Tokumaru et al, 2000;Ueda et al, 2005;Ueda et al, 2003). The radical scavenging properties operate in not only the ZNS-related antiepileptic activity but also its neuroprotective action against hypoxic/ischemic brain damage (Hayakawa et al, 1994;Owen et al, 1997).…”

“…However, subsequent pharmacological studies have demonstrated that the target molecules of ZNS include T-type voltage-sensitive Ca 2+ channel (Kito et al, 1996;Suzuki et al, 1992), Ca 2+ induced Ca 2+ releasing system (CICR) (Yamamura et al, 2009b;Yoshida et al, 2005), carbonic anhydrase (Yamamura et al, 2009a), redox (Tokumaru et al, 2000;Ueda et al, 2005;Ueda et al, 2003), neuronal depolarization-induced glutamate release (Okada et al, 1998;, enhancement of release of inhibitory neurotransmitters, e.g., GABA , dopamine and serotonin (Murakami et al, 2001;Okada et al, 1999;Okada et al, 1992;Okada et al, 1995) and lack of affinity to GABA A receptor (Rock et al, 1989). With regard to its antiparkinsonian action, ZNS enhances both the turnover and release of dopamine, and inhibits MAO-B activity and dopaminergic oxidative stress (Asanuma et al, 2008;Komatsu et al, 2000;Leppik, 2004;Mori et al, 1998;Murata, 2004;Okada et al, 1992;Okada et al, 1995;Ueda et al, 2005). While the typical dose of ZNS is 300 to 600 mg/day for patients with epilepsy (Seino et al, 1988), a significant improvement in motor symptoms is reported in patients of Parkinson's disease treated with only 25 to 100 mg/day of ZNS (Murata, 2004;Murata et al, 2007).…”

“…Current research associates free radical damage with epilepsy (Komatsu et al 1995;Sudha et al 2001), and the use of antioxidants early in the treatment of seizure-related neuronal injury is an attractive strategy, since epileptic seizures cause neuronal cell damage through the production of free radicals (Komatsu et al, 2000;Sudha et al, 2001). ZNS protects neurons against free-radical damage by scavenging the hydroxyl and nitric oxide radicals and such action is dose-dependent (Leppik, 2004;Mori et al, 1998;Noda et al, 1999).…”

Postoperative Seizures: Epidemiology, Pathology, and Prophylaxis

“…34,51) Oral administration of zonisamide, at clinically relevant doses, prevents the increase of lipid peroxide and 8-hydroxy-2'-deoxyguanosine, indicators of oxidative stress, induced by topical application of ferric chloride in rat cerebral cortex. 33) Effect of antiepileptic agents on immunity: The influence of antiepileptic agents on cellular immunity should be considered, especially in postoperative management of brain tumors. Phenytoin suppressed part of the cellular immune functions such as lymphocyte proliferation, natural killer activity, and cytotoxic T lymphocyte activity, and phenobarbital suppressed the proliferative response to interleukin-2 and cytotoxic T lymphocyte activity, but valproic acid suppressed no cellular immune activities.…”