It means that the observed positive significant association between study groups and serum level of CoQ10 was not attenuated after adjusting for age and sex of study subjects (
Table 2).
We also measured the association of seizure type (generalized seizures versus focal seizures) with serum concentration of CoQ10. Among the 39 recorded ES episodes, 28 attacks (71.8%) were focal seizures and 11 attacks (28.2%) were generalized convulsive seizures. No statistically significant correlation was found between the type of seizure and serum CoQ10 level.
Regarding the clinical features of epilepsy, we assessed the relationship between serum levels of CoQ10 and the frequency and duration of seizures using the Pearson correlation test. The mean seizure frequency was 11.92±21.21 attacks per month, and the epilepsy duration was 13.51±11.44 years. Interestingly, our results showed a negative significant correlation between duration of epilepsy and serum levels of CoQ10 (r = -0.37, P =0.02). A similar result was also detected when the correlation was examined between seizure frequency and levels of CoQ10 (r = -0.36, P=0.02).
4. Discussion
Oxidative stress triggered by diminished endogenous antioxidants or enhanced oxidants formation is currently considered as a possible mechanism underlying epileptic seizures (
Martinc, Grabnar, & Vovk, 2014). CoQ10 is a strong antioxidant that protects cells from oxidative damage through inhibiting certain enzymes involved in the formation of ROS and generating other antioxidants (
El-ghoroury et al., 2009;
Bhardwaj, & Kumar, 2016). However, the impact of CoQ10 on seizure characteristics in ES patients is not clear. In this study, we provide novel insights into the role of CoQ10 insufficiency in the pathophysiology of epileptic seizures. We demonstrate, for the first time, that serum concentration of CoQ10 decreases in ES patients. Our findings show that increasing the deficiency of CoQ10 results in more frequent and longer-lasting epilepsy.
It seems that the endogenous antioxidants and their repair capacity, which normally overcome the increased production of oxidants in cells, is reduced in ES patients. We thus assessed the serum levels of CoQ10, as an endogenous antioxidant, in these patients. Although baseline levels of CoQ10 could not be measured in the ES patients in our study, we found that their serum concentrations of CoQ10 were significantly lower than the control group. Decreased CoQ10 levels have also been shown to associate with various neurological diseases, including cerebral infarction, neurodegenerative processes, cerebral ataxia, and many other brain disorders (
Lamperti et al., 2003,
Spindler, Beal, & Henchcliffe, 2009;
Ramezani, Sahraei, Simani, Heydari, & Shahidi, 2020;
Simani, et al., 2018). CoQ10 deficiency could result in the enhancement of electrons transport to oxygen, which leads to the significant generation of superoxide anion (O2–) in mitochondria (
Chew, & Watts, 2004). It then may damage the cellular components due to the elevation of ROS and reduction in ATP production; however, the effect of insufficient CoQ10 in the former is more prominent in the pathogenesis of the diseases (
Lalkovičová and Danielisová 2016;
Milanlioglu et al., 2016). On the other hand, an increase in free radicals and a decrease in antioxidant level has been observed in the development of epilepsy (
Cengiz, Yüksel, & Seven, 2000;
Verrotti et al., 2002). Therefore, it is unclear what might underlie the decline of antioxidants such as serum CoQ10. Taken together, it can be postulated that an attenuated level of CoQ10 leads to a significant rise in ROS production, resulting in oxidative stress and thus neuronal damage in an epileptic brain.
To determine the potential role of CoQ10 in the type of seizures, we measured the correlation between these two variables. Based on our data, CoQ10 levels were not different in seizure types. This suggests that the type of epilepsy is unlikely to affect the serum concentration of CoQ10 in different ways. This finding is consistent with prior work showing no correlation between the activity of antioxidant enzymes or oxidative stress and types of seizures (
Yiş, Seçkin, Kurul, Kuralay, & Dirik, 2009).
This study provides clear evidence on a correlation between serum levels of CoQ10 and seizure frequency and duration of epilepsy. This issue may be related to free radical-mediated damage or a decrease in the activity of antioxidants caused by the deficiency of CoQ10 in ES patients (
Cengiz et al., 2000;
Verrotti et al., 2002). It has been shown that the risk of seizure recurrence increases with CoQ10 deficiency (
Yiş et al., 2009). An absolute or relative deficiency in CoQ10 results in a remarkable increase in the transfer of electrons to molecular oxygen in mitochondria, leading to the overproduction of superoxide free radicals (
Chew & Watts, 2004). The detrimental role of free radicals in seizures has been reported in rodent studies showing that antioxidants can reduce the oxidative stress markers in epileptic animals, accompanied by the decrease of their seizure manifestations (
Tan, Manchester, Reiter, Kim, & El‐Sokkary,1998;
Gupta, Briyal, & Chaudhary, 2002;
Mohanan, & Yamamoto 2002;
Barros et al., 2007;
Xavier et al., 2007).
Furthermore, the activity of CoQ10, as an antioxidant scavenger, inhibits lipid peroxidation (
Mancuso, Orsucci, Volpi, Calsolaro, & Siciliano, 2010). In this regard, findings from animal seizure models show that treatment of epileptic rats with CoQ10 exerts the neuroprotective effects by the removal of free radicals and reduction in lipid peroxidation levels and nitrite content, leading to ameliorate seizure severity (
de Sales Santos et al., 2010;
Tawfik, 2011). It has also been demonstrated that pretreatment with CoQ10 during the acute phase of pilocarpine-induced seizures results in lipid peroxidation reduction and antioxidant factors elevation, leading to an overall decrease in oxidative stress (
Santos et al., 2009).
Therefore, based on our results, the negative association between seizure frequency and duration of epilepsy with CoQ10 may be related to free radical-mediated damage triggered by a deficiency in CoQ10.
In conclusion, our study demonstrated significantly decreased levels of CoQ10 in ES patients. We also found that deficiency of CoQ10 would dramatically exacerbate the clinical features of epilepsy. These results suggest the development of novel methods of therapy, possibly including adjunctive antioxidant treatment. However, the study should be replicated in a larger sample of subjects.
Ethical Considerations
Compliance with ethical guidelines
This study was approved by the Medical Ethics Committee of Shahid Beheshti University of Medical Sciences (Core: IR.SBMU.RETECH.REC.1396.411). Written informed consent was obtained from all the participants.
Funding
This research did not receive any grant from funding agencies in the public, commercial, or non-profit sectors.
Authors' contributions
Conceptualization, investigation, and writing – original draft: Leila Simani and Omidvar Rezaei; Data collection: Fari Ryan, Masoumeh Sadeghi, Etrat Hooshmandi, and Mahtab Ramezani; Data analysis, Writing – review & editing: Leila Simani, Fari Ryan, Masoumeh Sadeghi, and Hossin Pakdaman.
Conflict of interest
The authors declared no conflict of interest.
Acknowledgments
We thank dr. Marjan Asadollahi, Mrs. Zohreh Afshar, and the Clinical Research Development Unit (CRDU) of Loghman Hakim Hospital and Shahid Beheshti University of Medical Sciences, Tehran, Iran for their support, cooperation, and assistance throughout the study period.
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