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Description: The effect of l -arginine and l -NAME on pentylenetetrazole induced seizures in ovariectomized rats, an in vivo study Mahmoud Hosseini a,. Hamid Reza Sadeghnia b,f Soodabeh Salehabadi c Hassan

The effect of l -arginine and l -NAME on pentylenetetrazole induced seizures in ovariectomized rats, an in vivo study

    Mahmoud Hosseini a,. Hamid Reza Sadeghnia b,f Soodabeh Salehabadi c Hassan Alavi d Ali Gorji e
    a Dept. of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran b Dept. of Pharmacology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran c Dept. of Biology, Faculty of Science, Islamic Azad University, Mashhad Branch, Mashhad, Iran d Dept. of Anatomy, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran e Institut fur Physiologie, Universitat Munster, 48149 Munster, Germany f Dept. of Modern Sciences and Technologies, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

Received 12 May 2009. Revised 19 September 2009. Accepted 24 September 2009. Available online 23 October 2009.

The role of ovarian hormones and nitric oxide (NO) on seizure and their interaction have been widely investigated. The present study carried out to evaluate the effect of chronic administration of l -arginine ( l A) and l -NAME ( l N) on pentylenetetrazole (PTZ) induced epilepsy in ovariectomized (OVX) and naïve female rats.

Fourty-eight female rats were randomly divided into six groups (n = 8) as follows: (1) sham, (2) ovarectomized (OVX), (3) sham- l A, (4) sham- l N, (5) OVX- l A, and (6) OVX- l N.

The animals of sham- l A and OVX- l A received daily injection of 500 mg/kg l -arginine (i.p.) during 4 weeks. Sham- l N and OVX- l N were treated by 10 mg/kg l -NAME (i.p.) daily for 4 weeks. The animals of sham and OVX groups received 1 ml/kg saline (i.p.) instead of l -arginine and l -NAME. The latencies to minimal clonic seizures (MCS) and generalized tonic–clonic seizures (GTCS) after intraperitoneal injection of penetylenetetrazole (PTZ, 90 mg/kg) was recorded and compared between groups.

A significant increase in the GTCS, but not MCS, latency was seen in OVX rats in comparison with sham-operated animals. Pretreatment of animals with l -NAME resulted in a significant increase in the GTCS and MCS latencies in sham group while no significant effects were seen in OVX rats. On the contrary, while pretreatment with l -arginine had no effects on MCS and GTCS latencies in sham group, a significant decrease in GTCS latency was observed in OVX rats.

It is concluded that ovarian sex hormones affect seizure thresholds induced by PTZ and NO has a role on seizures susceptibility following PTZ administration. This NO effect might be differing in the presence or absence of ovarian hormones, but further investigations need to be done.

Several studies have suggested a close link between sex hormones and epilepsy. 1 It seems that women with seizures that start in the temporal lobes of the brain more likely to have reproductive disorders such as polycystic ovaries, early menopause, and irregular (or no) ovulation, than women in the general population. 2 There is a close communication and connection between temporal lobes and the areas of brain (hypothalamus and pituitary gland) that regulate sex hormone secretion, so normal production of hormones may change by seizures. 3

There are many evidences showing the role of both male and female gonadal hormones on susceptibility in epilepsy. 4 It has been well documented that female and male sexual hormones alter the seizure threshold, the frequency and also symptoms of the seizures. 5 There are evidences that estrogens may increase neuronal excitability 6 while the results of other studies showed that progesterone had an anticonvulsant effect in animal models 7 and it also reduced seizures in human. 8 In men, sex hormones (testosterone and breakdown products) also influence brain functions and may have an impact on seizures. 3 and 9

Nitric oxide (NO), an important modulator of neuronal functions, is synthesized from l -arginine by NO synthase (NOS). 10 It can affect the release of other neurotransmitters such as glutamate, GABA and dopamine. 11 The role of this unconventional neurotransmitter in chemically and electrically induced seizures and human epilepsy has been widely reported. 12 and 13 It has been well documented that estrogen influences the NO system in both peripheral and nervous tissues. 14 and 15 It has been shown that estrogen increases eNOS activity and expression 16 and production of nitric oxide in endothelial cells. 17 There are evidences showing that estrogen changes nNOS mRNA and the number of nitergic neurons in brain regions such as hippocampus and influences NO production in the brain. 18

Therefore, the aim of the present study was to clarify the effects of l -arginine (the precursor of nitric oxide) and l -NAME (NOS inhibitor) on penetylenetetrazole (PTZ) induced seizures in ovariectomized and normal female rats.

Eight-week female Wistar rats (200 ± 10 g) were used. The animals were housed in 4–5 per standard cages, at room temperature (24 ± 1 °C) on a 12 h light/dark cycle. Food and water were available ad libitum properly. Animal handling and all related procedures were carried out in accordance with Mashhad University of Medical Sciences, Ethical Committee Acts.

l -Arginine, l -NAME and PTZ were purchased from Sigma Chemical (St. Louis, MO) and dissolved in normal saline. Ketamine was provided by Daroo-Pakhsh Pharm. (Tehran, Iran).

Rats were ovariectomized under ketamine anesthesia (150 mg/kg, i.p.). Anesthesia was confirmed by reduced respiratory rate and no response to gentle pinching of foot pad. Ventral incision was made through the skin of the flank of the rat and ovaries and ovarian fats were removed. Ovaries were isolated by ligation of the most proximal portion of the oviduct before removal. The animals were reversed to their cages to recover from surgery. 19

In order to observe ictal behavior, PTZ (90 mg/kg, i.p.) was injected and the animals were placed in plexiglas arena (30 cm × 30 cm × 30 cm) on the day of the experiment. The animals were observed during 60 min after PTZ administration. Behavioral responses of the animals to PTZ administration were evaluated using these criteria: latency to first minimal clonic seizure (MCS), incidence of MCS, latency to the first generalized tonic–clonic seizures (GTCS), incidence of GTCS, protection percentage against GTCS and protection percentage against mortality. 20

Fourty-eight rats were divided into six groups (n = 8) as follows: (1) sham, (2) ovariectomized (OVX), (3) sham- l A, (4) sham- l N, (5) OVX- l A, and (6) OVX- l N.

The animals of sham- l A and OVX- l A received 500 mg/kg l -arginine 21 and 22 every day during 4 weeks. The animals of sham- l N and OVX- l N groups received 10 mg/kg l -NAME 23 every day during 4 weeks. 24 The animals of sham and OVX groups received 1 ml/kg saline instead of l -arginine and l -NAME every day during 4 weeks. Finally, the animals of all treatment groups were injected by PTZ (90 mg/kg) 24 h after last injection and behavioral criteria were evaluated. All injections were carried out intrapritoneally between 10 and 12 AM.

Data are expressed as mean ± SEM. Fisher's exact probability test, as well as analysis of variance, followed by Tukey test, were used for statistical evaluation. The p -values less than 0.05 were considered to be statistically significant.

All animals in different treatment groups were showed MCS and GTCS following PTZ administration. A significant increase (p < 0.001) in the GTCS (Fig. 2 ), but not MCS (Fig. 1 ), latency was seen in ovariectomized (OVX) rats in comparison with sham-operated animals. The GTCS latencies in sham and OVX groups were 67.0 ± 2.8 s and 117.0 ± 13.4 s respectively (Fig. 2 ). Pretreatment of animals with l -NAME ( l N) significantly increased the GTCS and MCS latencies in sham group (p < 0.001) while no significant effects were seen in OVX rats (Fig. 1 and Fig. 2 ). On the contrary, while pretreatment with l -arginine ( l A) had no effects on MCS and GTCS latencies in sham group, a significant decrease (117.0 ± 13.4 s vs. 75.8 ± 6.7 s; p < 0.01) in GTCS latency was observed in OVX rats (Fig. 1 and Fig. 2 ). A similar, but statistically not significant, decrease was also seen in MCS threshold following l A pretreatment in OVX rats (Fig. 1 ). There were no significant differences in mortality rate following PTZ administration between different treatment groups.

Fig. 1. Latencies to minimal clonic seizures (MCS) onsets in sham, OVX, sham- l A, sham- l N, OVX- l A and OVX- l N groups. Data are presented as mean ± SEM (n = 8 in each group). ***p < 0.001 as compared to sham group. Analysis of variance (ANOVA), followed by Tukey test, were used for statistical evaluation.

Fig. 2. Latencies to generalized tonic–clonic seizures (GTCS) onsets in sham, OVX, sham- l A, sham- l N, OVX- l A and OVX- l N groups. Data are presented as mean ± SEM (n = 8 in each group). ***p < 0.001 as compared to sham group, ## p < 0.01 as compared to OVX group. Analysis of variance (ANOVA), followed by Tukey test, were used for statistical evaluation.

Modulatory effects of sex hormones on brain functions as well as neurological disorders such as Parkinson, Alzheimer and epilepsy have been reported. 25 and 26 It has been shown that gender-specific sex hormones affect seizure threshold and frequency. 27 In normal ovulatory cycles, seizure frequency in some women with epilepsy exhibits a positive correlation with a high serum estradiol/progesterone ratio. 28 and 29 Sex dependence differences in the severity of seizures have also been reported. 27 and 30 Moreover, it has been shown that nitric oxide might have a role in these differences. 30

Menopause did influence seizure patterns. 31 OVX rats have been frequently used as a model of hormone deprivation to study post-menopausal changes in adult females. In this study, ovariectomy resulted in a significant decrease in PTZ-induced seizures susceptibility. The results of present study are in agreement with previous studies showing that estrogen increases neuronal excitability and may act as a proconvulsant. 32 While, progesterone has inhibitory effect and increases the seizure threshold, slowing kindling and decreasing seizure susceptibility. 29 and 33 However, Hoffman et al. reported that administration of estrogen had no effect on kainic acid (KA)-induced seizures severity in rat. 34 Pereira et al. also showed that estrogen replacement therapy attenuated frequency of seizures in piliocarpine induced epilepsy model. 35 Velísková et al. also showed that estrogen treatment before KA administration significantly delayed the onset of KA-induced clonic seizures and reduced mortality, whereas it had no effects on the onset of status epilepticus. 36 and 37 All of these data confirms that sex hormones might have a role in seizure susceptibility. Sex differences in seizure susceptibility have been attributed to the effects of sex hormones on central nervous system 27 and 30 however, the exact mechanism has not been well known. There are increasing evidences showing that the sex hormones exert their regulatory effects on neuronal excitability, by modulating neurotransmitters receptors including GABAA. NMDA, opioid receptors, as well as by directly and/or indirectly adenosine receptors. 38. 39. 40 and 41 Inhibitory effects of estradiol in physiological doses on GABA neurotransmission as well as GABA synthesis and release has also been reported. 42 and 43 The higher susceptibility of OVX rats to PTZ-induced seizure which was seen in the present study might be interpreted by these mechanisms. On the other hand, the effect of NO on sex hormone-dependent behavioral changes of female rats has also been reported. 23 We hypothesized that the NO signaling pathway may, at least in part, contribute in seizure susceptibility differences between OVX and naïve female rats. For this reason, the chronic effects of l -arginine ( l A), the precursor of nitric oxide, and l -NAME ( l N; a NOS inhibitor) on PTZ-induced seizures in ovariectomized and naïve female rats were also investigated. While l N delayed latency of PTZ-induced seizures in naïve female rats, it had no significant effects in OVX rats. On the contrary, l A fastened the onset of PTZ-induced seizures in OVX rats.

In the brain, NO acts as a neuronal messenger and a modulator of neurotransmission. 44 It has been documented that NOS substrates, NO donors, and NOS inhibitors exert various anticonvulsant 45 and 46 or proconvulsant 47 and 48 effects in different seizure models. Bosnak et al. (2007) showed that systemic administration of l -arginine significantly decreased the frequency of epileptiform electrocorticographical (ECoG) activity on penicillin-induced seizures in male rats while it did not modulate anti-seizures activity of pyridoxine and clonazepam. 22 and 49 However, a proconvulsant activity for l -arginine has also been reported. 48 Noyan et al. (2007) showed that central administration of l -NAME had no effects on the latency and severity of seizures following pillocarpine injection. 50 It has also been reported that while systemic administration of l -NAME (non-specific NOS inhibitor) had no effects on penicillin-induced seizures in male rats, but 7-nitroindazole (7-NI, a nNOS inhibitor) significantly decreased epileptiform ECoG activity. 22 Another research showed that N-omega-nitro- l -arginine (NNA), an inhibitor of NOS, aggravated KA-induced seizures. 13 A functional relationship between the NO-cGMP signaling pathway and the anticonvulsant activities of adenosine and pyridoxine has also been suggested. 22 and 51 The result of present study also confirmed that NO system has a role in PTZ induced seizures.

It was documented that ovariectomy reduced neuronal (nNOS) and endothelial NO synthase (eNOS) expression and Ca 2+ -dependent NOS activity, which was reversed by 17 beta-estradiol repletion. It was concluded that estradiol increases nNOS and eNOS expression and activity in female hippocampus. 18 Therefore, different effects of l A and l N on PTZ-induced seizures in OVX and naïve rats in the present study could be explained by reduced NOS activity and NO production after ovariectomy. Recently, Gholipour et al. (2008) also demonstrated that l -NAME augments the anticonvulsive activity of progesterone, whereas l -arginine significantly blunts this effect of progesterone in OVX mice. 29 On the other hand, Uzüm et al. (2005) reported that pretreatment with l -NAME completely prevented PTZ-induced seizures in male rats, whereas increased severity, frequency, duration, had significantly shortened the latency in female rats. Unexpectedly, NO donor, sodium nitroproside (SNP) increased convulsion severity, frequency, duration, and shortened latencies in male rats, while the reverse effects were seen in the females. They concluded that sex-dependent differences in seizures severity might be related to NO. 30 All of these data confirm that there are potential levels of interaction between sex hormones and the NO signaling systems in the regulation of seizure susceptibility.

In conclusion, the results of present study showed that NO has a role on seizures susceptibility following PTZ administration and this effect might be different in the presence or absence of ovarian hormones, but further investigations need to be done.

Authors would like to thank the Vice Chancellor of Research Affairs of Mashhad University of Medical Sciences, for financial supports.

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