Memantine up-regulates nicotinic acetylcholine receptors expression in the cortex and sub-cortical white matter of aging rat brain

• Autorzy: Polrolniczak A. , Rozycka A. , Helias-Rodzewicz Z. , Kempisty B. , Grzelak T. , Ziemnicka K. , Steinborn B. , Jagodzinski P. P. , Dorszewska J.
• Języki publikacji: EN

Abstrakty

EN

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.

Słowa kluczowe

EN

memantine; N-methyl-D-aspartate receptor; receptor expression; cortex; subcortical white matter; rat; brain; acetylcholine receptor

• Wydawca: -
• Czasopismo: Acta Neurobiologiae Experimentalis
• Rocznik: 2013
• Tom: 73
• Numer: 1
• Opis fizyczny: p.170

Twórcy

autor

Polrolniczak A.

• Laboratory of Neurobiology, Department of Neurology, Poznan University of Medical Sciences, Poznan, Poland

autor

Rozycka A.

• Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Poznan, Poland

autor

Helias-Rodzewicz Z.

• Department of Pathology, University of Versailles, Boulogne, France

autor

Kempisty B.

• Department of Histology and Embryology, Poznan University of Medical Sciences, Poznan, Poland

autor

Grzelak T.

• Department of Chemistry and Clinical Biochemistry, Poznan University of Medical Sciences, Poznan, Poland

autor

Ziemnicka K.

• Laboratory of Neurobiology, Department of Neurology, Poznan University of Medical Sciences, Poznan, Poland

autor

Steinborn B.

• Department of Developmental Neurology, Poznan University of Medical Sciences, Poznan, Poland

autor

Jagodzinski P. P.

• Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Poznan, Poland

autor

Dorszewska J.

• Laboratory of Neurobiology, Department of Neurology, Poznan University of Medical Sciences, Poznan, Poland