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The α-4 subunit gene (CHRNA4) of the neuronal nicotinic acetylcholine receptor (nAChR), linked to an idiopathic partial epilepsy, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), may also play a key role in the development of the idiopathic generalized epilepsy syndrome (IGE), juvenile myoclonic epilepsy (JME). This study was designed to explore an association of four polymorphisms of the CHRNA4 with JME in Polish children and young patients. The study included 92 JME patients and 222 unrelated healthy individuals. In each group the frequencies of the CHRNA4 c.555C>T, c.594C>T, 1674+11C>T, and 1674+14A>G polymorphisms were determined using PCR-RFLP analyses. An association between the 1674+11C>T polymorphism of the CHRNA4 and JME was evidenced. Allele T (the risk factor) appeared with a significantly higher frequency in the JME patients than in the controls (p=0.0299). The patients harboring the 1674+11CT+TT genotypes showed an increased risk of JME (CT+TT versus CC: OR=1.925; 95% CI=1.021-3.629; p=0.0408). No association was found for the other CHRNA4 polymorphisms tested. The CHRNA4 1674+11C>T polymorphism may be a susceptibility factor for epilepsy, and its higher frequency in patients with juvenile myoclonic epilepsy suggests that the CHRNA4 may be one of the candidate genes for this epileptic syndrome.
Aging is accompanied by a high level of oxidized form of guanine, 8-oxo-2’deoxyguanosine (8-oxo-2’dG), and decreased level of 8-oxoguanine glycosylase 1 (OGG1) in the brain. The development and progression of neurodegenerative disorders are also characterized by dysfunction or loss of the brain nicotinic acetylcholine receptors (nAChRs). To study whether the differences in nAChRs expression in the rat brain occur due to aging or oxidative stress we analyzed RNA and protein levels of α7, α4 and β2 subunits by RQ-PCR and Western blot validation in three brain structures: cerebral grey matter (CGM), sub-cortical white matter (SCWM) and cerebellum (Ce) of twenty one female Wistar rats. The first group consisted of five 3.0–3.5-month-old females, which was assigned as a young control group. The remaining sixteen females aged of 18–24 month were divided into three following groups: (1) aged control group of 5 rats; (2) a vehicle group of 5 rats which received intraperitoneal injections of deionized water; (3) memantine-treated group of 6 rats. In each group, the selected brain areas have also been analyzed to determinate the levels of oxidative stress. In this study, age- and stress- dependent differential RNA and protein expression levels were approved only in OGG1 and α7 nAChR proteins. In all analyzed brain structures of young and old controls, the levels of oxidized form of guanine were similar. Stress relevant to water injection increased the level of 8-oxo-2’dG in the cerebellum of old control rats (Ce, P<0.05). The old controls demonstrated an important reduction of OGG1 mRNA expression in CGM and Ce regions compared to young individuals (CGM P=0.03; Ce P=0.2). Western blot analysis has also revealed a reduction of OGG1 protein in the sub-cortical white matter of old individuals (SCWM, P=0.03). However, there was no important influence of water administration on OGG1 expression in all brain regions. In all analyzed brain structures, expression of α7 nAChR was down-regulated in old controls compared to young controls. However, this decrease was only significant in SCWM area (SCWM, P<0.05). Treatment with H2O caused a significant increase in RNA and protein levels of α7 nAChR in SCWM as compared to this brain structure of the aged control rats (SCWM, P<0.01). Our results suggest that aging of the rat brain is mostly associated with decreased expression of OGG1 as well as with deficit of α7 nAChR in the sub-cortical white matter. Stress relevant to water injection increases the level of 8-oxo-2’dG in the aging rat brain, but clearly overcomes the α7 nAChR deficit. A significant increase of the α7 nAChR expression in the SCWM of H2O-treated rats suggests that these receptors play an important role in compensatory mechanisms facilitating the impaired cholinergic neurotransmission following oxidative stress in the aging rat brain.
Memantine (MEM) is a potent open channel blocker of N-methyl-Daspartate receptors (NMDARs), and primary has been developed for treatment of neuropathic pain, symptoms of dementia and AD. On the other hand, MEM is able to act as an open channel blocker on several other ligand gated ion channels, e.g., the α4β2 and α7 nicotinic acetylcholine receptors (nAChRs). The aged-related decline in the nAChRs expression could be associated with other senescence markers, such as increased oxidative stress leading to oxidative DNA changes (high level of 8-oxo-2’dG), accompanied with significant decrease in level of the OGG1 protein involved in DNA repair process. To study whether MEM treatment might influence on the α7 and α4 nAChRs expression in the aging rat brain tissues, we analyzed RNA and protein levels by RQ-PCR and Western blot validation in three brain structures: cerebral grey matter (CGM), sub-cortical white matter (SCWM) and cerebellum (Ce) of twenty one female Wistar rats. The animals were divided into following experimental groups: the first group consisted of five 3.0–3.5-month-old females, which was assigned as a young control group, and the remaining sixteen females aged of 18–24 month were divided into three following sub-groups: (1) aged control group of 5 rats; (2) a vehicle group of 5 rats which received intraperitoneal injections of deionized water (3) memantine-treated group of 6 rats. In each group, the selected brain areas have also been analyzed to determinate the levels of oxidative stress. In CGM and SCWM brain structures the level of 8-oxo-2’dG was significantly reduced in old rats after MEM administration (CGM P=0.05; SCWM P<0.05). Western blot analysis has also revealed a significant up-regulation of OGG1 level in CGM after MEM administration (CGM P=0.05). MEM specifically up-regulated mRNA level of cortical α4 subunit in the CGM region of aging rat brain (CGM, P<0.05). In the sub-cortical white matter an important increase of α7 mRNA level has been observed after MEM administration (SCWM P<0.05). The level of α7 nAChR protein was significantly up-regulated also in CGM and Ce regions of MEM treated rats (SCWM P=0.05; CGM P<0.05; Ce P<0.05). We demonstrated that processes related to aging, such as a decreases in OGG1 and nAChRs expression can be modified after memantine administration: (1) A significant increase in the CGM of α4 and α7 subunits, as well as up-regulated α7 level in the SCWM after MEM administration suggests that nAChRs play an important role in compensatory mechanisms facilitating the impaired cholinergic neurotransmission following treatment with MEM. (2) MEM significantly up-regulates cortical OGG1 protein expression and reduces the level of 8-oxo-2’dG in CGM. (3) A significant increase in both mRNA and protein levels of α7 nAChR along with reduction of 8-oxo-2’dG in SCWM, following treatment with MEM, suggests that the effect of MEM on cholinergic function may be associated with antioxidant mechanisms. Whether these protective effects of MEM are direct or are mechanistically remote from NMDARs antagonism, have to be evaluated in the further studies.
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