Nitric oxide and interlukin-6 levels in intellectual disability adults with epilepsy

doi:10.1016/j.ridd.2008.08.004

Research in Developmental Disabilities

Volume 30, Issue 3, May–June 2009, Pages 567-571

https://doi.org/10.1016/j.ridd.2008.08.004 Get rights and content

Abstract

Nitric oxide (NO) and interlukin-6 (IL-6) are highly reactive mediators that have been shown to play different roles in a variety of different biological process. The role of NO and IL-6 in the neuropathogenesis of brain seizures is still questionable. In order to evaluate the role of NO and IL-6 in neurological disorders such as seizures, we investigated 19 adults with intellectual disability (ID) who suffer from epilepsy and treated for convulsions. NO metabolites (NOx) and IL-6 levels in serum obtained after night-sleep were significantly high among ID individuals diagnosed with epilepsy versus ID people without epilepsy. These results indicated that NOx and IL-6 may have a pathophysiological role in convulsions. Consequently, we suggest that professionals consider chemical inhibitors that might be helpful against the function of NO and IL-6.

Section snippets

Participants

The sample consisted of permanent residents who lived in residential care center. After being referred to the study by the institutional health-care medical doctor, only candidates that answer the three inclusion criteria were used in the experimental group: (1) mild intellectual deficiency, as diagnosed within 1–3 years after birth by IQ-scores defined by the Wechsler Abbreviated Scale of Intelligence (Harcourt Assessment Inc., San Antonio); (Hays, Reas, & Shaw, 2002). (2) Epilepsy, diagnosed

Results

Secretary protein in serum was examined for IL-6 and NO expression by nitrites level in order to investigate inflammatory status. The transcription of pro-inflammatory IL-6 cytokine was significantly increased in serum among epileptic individuals compared to control group (P < 0.005). Additionally, NOx levels were higher (P < 0.05) in the experimental group compared the control group (Table 1). The serum levels of IL-6 correlated significantly with NOx levels of the same participants at the same

Discussion

Although numerous studies have examined the effects epileptic attacks have on function, little attention has been paid to understand the pathological mechanisms responsible for cerebral damage which may lead to cognitive impairment. The frequency of epilepsy among ID individuals increases with age, and may be as high as 50% based on a 4-year retrospective survey of ID people live in residential care centers (Merrick, Kandel, & Stawski, 2006). It is known that epilepsy can affect neuronal cells

References (13)

O. Dammann et al.
Infection remote from the brain, neonatal white matter damage, and cerebral palsy in the preterm infant
Seminar in Pediatric Neurology
(1998)
M. Fritzenwanger et al.
Cardiotrophin-1 induces interleukin-6 synthesis in human monocytes
Cytokine
(2007)
H. Hamano et al.
Regulation of brain cell environment on neuronal production: Role of TNFα in glia cells
Life Sciences
(2002)
I. Miura et al.
Hydrogen peroxide induced chemokine production in the glia-rich cultured cerebellar granule cells under acidosis
Life Sciences
(2002)
X. Chen et al.
Serum levels of nitric oxide metabolites during labour with or without combined spinal-epidural analgesia
European Journal of Anaesthesiology
(2008)
G.A. Czapski et al.
Role of nitric oxide in the brain during lipopolysaccharide-evoked systemic inflammation
Journal of Neuroscience Research
(2007)

There are more references available in the full text version of this article.

Cited by (19)

Proconvulsant effects of Nepeta menthoides hydro alcoholic extract in different seizure tests: behavioral and biochemical studies
2020, Heliyon
Citation Excerpt :
It is shown that large amounts of nitric oxide induce limbic seizures. There is also evidence attributing hippocampal neuron damage to rises in the release of glutamate and nitric oxide [72]. However, the role of NO is unknown in the pathophysiology of epilepsy.
In Iran, both Nepeta menthoides - the endemic species of Nepeta genus - and Lavandula officinalis are known as Ustukhuddoos and used widely as medicinal herbs. In Iranian traditional medicine, Ustukhuddoos has been recommended for several neuronal diseases including depression and epilepsy. While the antiepileptic effects of Lavandula officinalis have been investigated in a number of studies, no reports are available taking into account the effect of Nepeta menthoides on epilepsy. Since convulsion is an important side effect of some medicinal plants, a thorough study of the effects of Nepeta menthoides on epilepsy seems necessary.
This study was designed to investigate the potential anti- or pro-convulsant activity of Nepeta menthoides and its effects on oxidative stress markers. Since an herbal medicine showed opposite effects in two animal models of epilepsy in our laboratory, authers decided to study Nepeta effects through several seizure tests including the intravenous pentylenetetrazol (i.v. PTZ) infusion, the maximal electroshock (MES), acute PTZ and PTZ-kindling tests. These seizure models are generally used for screening pro- or anti-epileptic drugs. Nepeta menthoides (400 mg/kg) significantly reduced the dose of PTZ necessary for clonus seizure induction. Combining either phenytoin (Phen) or Valproate (Val) with Nepeta decreased their antiepileptic effects. Therefore, Nepeta menthoides not only failed to prevent the seizures but also increased sensitivity to them. Nepeta raised brain NO levels in different seizure tests. It seems there is a relation between NO elevation by Nepeta and increased sensitivity to seizures that should be investigated later.
MnSOD Ala16Val polymorphism in cognitive dysfunction in patients with epilepsy: A relationship with oxidative and inflammatory markers
2020, Epilepsy and Behavior
Citation Excerpt :
Therefore, considering the molecular changes mentioned above, it is plausible to suggest that they may be associated with cognitive deficit in epilepsy. Reinforcing what was previously described, one of the hypotheses that explains cognitive dysfunctions, such as memory impairment, includes changes in gene expression, epigenetic effects of seizures [30], remodeling of the immunological system, and activation of inflammatory markers [7,33]. Data in the literature have estimated that genetic factors account for approximately 50% of the variability in human memory capacity [10] and impairment of cognition in epilepsy may likely be a consequence of interacting genetic, epigenetic, developmental, and environmental factors [32].
The objective of the study was to evaluate the neurocognitive profile and its relation with Ala16ValMnSOD polymorphism in epilepsy and if these clinical parameters are linked to oxidative stress and inflammatory markers.
Patients with epilepsy (n = 31) and healthy subjects (n = 42) were recruited. A neuropsychological evaluation was performed in both groups through a battery of cognitive tests. Oxidative stress, inflammatory markers, apoptotic factors, and deoxyribonucleic acid (DNA) damage were measured in blood samples.
Statistical analyses showed the association of MnSOD Ala16Val polymorphism with cognitive impairment, including praxis, perception, attention, language, executive functions, long-term semantic memory, short-term visual memory, and total memory in patients with epilepsy and Valine-Valine (VV) genotype compared with the control group. Compared with the controls and patients with epilepsy, Alanine-Alanine (AA), and Alanine-Valine (AV) genotype, the patients with epilepsy and VV genotype exhibited higher levels of tumor necrosis factor alpha (TNF-α), interleukin 1β (IL-1β), interleukin 6 (IL-6), activation of caspases 1 and 3 (CASP-1 and -3), and DNA damage. Our findings also showed higher carbonyl protein and thiobarbituric acid reactive substances (TBARS) levels as well as an increased superoxide dismutase (SOD) and acetylcholinesterase (AChE) activities in patients with epilepsy and VV genotype.
This study supports the evidence of a distinct neuropsychological profile in patients with epilepsy, especially those with the VV genotype. Furthermore, our results suggest that oxidative and inflammatory pathways may be associated with genetic polymorphism and cognitive dysfunction in patients with epilepsy.
Depressive, inflammatory, and metabolic factors associated with cognitive impairment in patients with epilepsy
2018, Epilepsy and Behavior
Citation Excerpt :
Results found showed that from the total number of patients with epilepsy evaluated in the depression test, 65.6% presented different levels of depression. The authors also reported that the comorbidity and complications of epilepsy, including depression and intellectual disability, may be related to cytokine pathways [43–45]. Brain inflammation has been implicated in the pathophysiology of various neuropsychiatric conditions.
The purpose of this study was to examine the cognitive function and depressive traits most frequently associated with the clinical assessment of patients with epilepsy and if these clinical parameters are linked to glycolipid levels and inflammatory and apoptotic markers.
Patients with epilepsy (n = 32) and healthy subjects (n = 41) were recruited to participate in this study. Neuropsychological evaluation was performed in both groups through a battery of cognitive tests. Inflammatory markers, apoptotic factors, and deoxyribonucleic acid (DNA) damage were measured in blood samples. Additionally, the metabolic markers total cholesterol (CHO), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglyceride (TG), and glucose (GLU) levels were analyzed.
Statistical analyses showed that patients with epilepsy presented decreased scores in memory, attention, language, and executive function tests compared with the control group. Analysis revealed that there was negative correlation in epilepsy for seizure duration vs. oral language (R = − 0.4484, p < 0.05) and seizure duration vs. problem solving (executive functions) (R = − 0.3995, p < 0.05). This was also observed when comparing depression with temporal–spatial orientation (TSO) (R = − 0.39, p < 0.05). Furthermore, we observed a higher depression score in patients with epilepsy than in the healthy ones. Statistical analyses showed higher acetylcholinesterase (AChE) (p < 0.05), interleukin 1β (IL-1β, p < 0.001), and tumor necrosis factor-alpha (TNF-α) (p < 0.001) levels compared with those in the control group. Moreover, patients with epilepsy had significantly higher serum levels of caspase 3 (CASP 3) (p < 0.001) and Picogreen (p < 0.001) compared with the control subjects. Regarding the metabolic markers, higher glycolipid levels were observed in the patients with epilepsy (CHO < 0.05*, LDL < 0.0001*, TG < 0.05*, GLU p < 0.05). High-density lipoprotein levels were not significant. The patients with epilepsy had significant correlation when comparing total language with TNF-α (R = − 0.4, p < 0.05), praxes with CASP 3 (R = − 0.52, p < 0.01), total CHO with total language (R = − 0.48, p < 0.05), TG with semantic memory (R = − 0.54, p < 0.05), TG with prospective memory (R = − 0.2165, p < 0.02), TG with total memory (R = − 0.53, p < 0.02), and GLU with total attention (R = − 0.62, p < 0.002).
This study supports the evidence of a distinct neuropsychological profile between patients with epilepsy and healthy subjects. Furthermore, our findings suggest that inflammatory pathway, glycolipid profile, and depressive factors may be associated with cognitive dysfunction in patients with epilepsy.
Cytokine levels in febrile seizure patients: A systematic review and meta-analysis
2018, Seizure
Febrile seizures (FSs) are the most common form of childhood seizures. During infection, both pro-inflammatory and anti-inflammatory cytokines are produced. Complex interactions among immune-inflammatory process, cytokine activation, and genetic factors are involved in the pathogenesis of FSs. The association between cytokines and FSs during childhood is inconclusive due to inconsistent results reported in different studies. We performed a systematic review and meta-analysis to determine an association between cytokines and FS in children.
We searched PubMed, EMBASE, and Cochrane databases for studies published up to January 2017 using the following key words: [“cytokine” OR “interleukin” OR “tumor necrosis factor alpha” OR “interferon-gamma” OR “single nucleotide polymorphism”] AND [“febrile seizure” OR “febrile convulsion”] AND [“pediatric” OR “infant” OR “child”]. Standardized mead difference (SMD) and 95% confidence intervals (CI) were calculated using standard meta-analysis techniques.
A total of 6 studies enrolling 243 children with FS and 234 controls were included in the meta-analysis. A total of 4 different inflammatory mediators were. The results indicated that CSF IL-1β level and serum IL-6 level were significantly associated with FS (CSF IL-1β: SMD, 1.064; 95% CI, 0.217–1.611; P < 0.01, serum IL-6 SMD, 2.654; 95% CI, 2.332–2.975; P < 0.01).
The results of this meta-analysis suggest that CSF IL-1β level and serum IL-6 level are associated with an increased risk of FSs in children. Based on these results, it is expected that a therapeutic agent for specific cytokines could be developed in the future to prevent FS.
PDEI-5 for Erectile Dysfunction: A Potential Role in Seizure Susceptibility
2012, Journal of Sexual Medicine
There is a high prevalence of erectile dysfunction (ED) in men with epilepsy; however, few studies have been conducted concerning the treatment of ED in this neurological group.
The main purpose of this review is to highlight the influence of phosphodiesterase type 5 inhibitor (PDEI‐5) for ED on seizure susceptibility.
All available online articles with information pertaining to PDEI‐5 and seizure susceptibility were included in this review.
The main outcome assessed demonstrated the intriguing role of PDEI‐5 and its metabolites on seizure susceptibility.
Case reports in men without epilepsy described seizure occurrence and electrophysiological changes following sildenafil, tadalafil, or vardenafil treatment. Consistent with these findings, preclinical studies suggested a proconvulsant effect of PDEI‐5 on models of seizure induction.
Evidence suggests an influence of PDEI‐5 on seizure susceptibility in humans. In addition, preclinical studies have demonstrated the role of nitric oxide metabolites in the facilitation of paroxysmal phenomenon. Although there are many causes of seizures, medical professionals should be aware of the possible influence of PDEI‐5 on seizure susceptibility. Further investigation by physicians and scientists is required to improve our understanding of this important topic. Matos G, Scorza FA, Cavalheiro EA, Tufik S, and Andersen ML. PDEI‐5 for erectile dysfunction: A potential role in seizure susceptibility. J Sex Med 2012;9:2111–2121.
A meta-analysis of pro-inflammatory cytokines in the plasma of epileptic patients with recent seizure
2012, Neuroscience Letters
Citation Excerpt :
Some non-drug treatments of epilepsy, such as surgery [16], vagus nerve stimulation [31], and ketogenic diet [2,53], had significantly effects on the levels of pro- and anti-inflammatory cytokines. Last, the comorbidity and complications of epilepsy, such as depression [13,33] and intellectual disability [9], may also influence the production and release of cytokines. It is also possible that the duration, sex, and age of epilepsy patients may have an impact on these cytokine levels.
This review was to assess the concentration changing trends of various cytokines in plasma of epilepsy patients after recent seizure, as well as to assess the differences between temporal lobe epilepsy (TLE) and extra-TLE (XLE) patients. We performed a meta-analysis of studies measuring cytokine concentration in plasma of patients suffering from epilepsy after recent seizure, by searches of the English literature in Pubmed and Embase databases (to July 1st 2010) and a manual search of references. A random-effects model was used to do accumulative analysis for the included studies by RevMan 5.0 software. Eight studies were included and analyzed. We found the plasma concentrations of interleukin-6 (IL-6) within 72 h after seizure were significantly increased in epileptic patients compared with control subjects (211 epilepsy patients vs. 564 controls, overall weighted mean difference 1.27 pg/ml, 95% confidence interval 0.72–1.82, P < 0.0001). There were no significant differences for IL-1 beta and, IL-1 receptor antagonist (IL-1RA) between the two groups. The concentration changes of IL-6 and IL-1RA were not significantly different between TLE patients and XLE patients. The result of this meta-analysis revealed significantly higher concentrations of the pro-inflammatory cytokines IL-6 in epileptic seizure patients compared with control subjects. Further rigorous studies are needed to clarify the precise role of cytokines in epilepsy.

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Nitric oxide and interlukin-6 levels in intellectual disability adults with epilepsy

Abstract

Section snippets

Participants

Results

Discussion

Seminar in Pediatric Neurology

Cytokine

Life Sciences

Life Sciences

Serum levels of nitric oxide metabolites during labour with or without combined spinal-epidural analgesia

European Journal of Anaesthesiology

Role of nitric oxide in the brain during lipopolysaccharide-evoked systemic inflammation

Journal of Neuroscience Research