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Similar cation channels mediate protection from cerebellar exitotoxicity by exercise and inheritance.

Ben-Ari S, Ofek K, Barbash S, Meiri H, Kovalev E, Greenberg DS, Soreq H, Shoham S - J. Cell. Mol. Med. (2012)

Bottom Line: Sedentary FVB/N and exercised C57BL/6 mice both expressed higher levels of these cation channels compared to sedentary C57BL/6 mice, and were both found to be less sensitive to glutamate toxicity.In addition, our findings highlight the involvement of the cholinergic anti-inflammatory pathway in insult-inducible cerebellar processes.These mechanisms are likely to play similar roles in other brain regions and injuries as well, opening new venues for targeted research efforts.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel.

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Related in: MedlinePlus

Kir6.1 channel protects the cerebellum from kainate damage. (A) Cerebellar Kir6.1 levels. Both types of exercise (EC and TM) significantly enhanced Kir6.1 expression, and the basal Kir6.1 levels were higher in FVB/N than C57BL/6 (C57) mice (semi-quantification is based on percentage of Kir6.1 immunoreactive stained area, control value is 3.6%, *P < 0.0005, post-hoc analysis after one-way ANOVA, #P < 0.005 in comparison to sedentary C57BL/6 mice, Student’s t-test, n ∇ 6–9 per group). (B) Glibenclamide augments Kainate damage. Sagittal cerebellar slices were treated for 20 min. with either DMSO or glibenclamide (gli, 20 nM) and then with or without 20 μM kainate (30 min.). Shown are Purkinje cells stained with Flurojade B 5.5 hrs after treatment. Top: Semi-quantification is based on staining intensities normalized to background staining, as measured by Image J and control value of 95.1 arbitrary units, n ∇ 4–8 mice per treatment group, *P < 0.0005 in comparison to naïve mice, post-hoc analysis after two-way ANOVA. Bottom: Distribution histograms of Flurojade B staining intensity in each treatment group. The distributions are significantly distinct from each other (P < 0.05, Kolmogorov–Smirnov test, a.u.: arbitrary units). Note enhanced neuronal degeneration after kainate injection, and its augmentation by glibenclamide pre-treatment.
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fig03: Kir6.1 channel protects the cerebellum from kainate damage. (A) Cerebellar Kir6.1 levels. Both types of exercise (EC and TM) significantly enhanced Kir6.1 expression, and the basal Kir6.1 levels were higher in FVB/N than C57BL/6 (C57) mice (semi-quantification is based on percentage of Kir6.1 immunoreactive stained area, control value is 3.6%, *P < 0.0005, post-hoc analysis after one-way ANOVA, #P < 0.005 in comparison to sedentary C57BL/6 mice, Student’s t-test, n ∇ 6–9 per group). (B) Glibenclamide augments Kainate damage. Sagittal cerebellar slices were treated for 20 min. with either DMSO or glibenclamide (gli, 20 nM) and then with or without 20 μM kainate (30 min.). Shown are Purkinje cells stained with Flurojade B 5.5 hrs after treatment. Top: Semi-quantification is based on staining intensities normalized to background staining, as measured by Image J and control value of 95.1 arbitrary units, n ∇ 4–8 mice per treatment group, *P < 0.0005 in comparison to naïve mice, post-hoc analysis after two-way ANOVA. Bottom: Distribution histograms of Flurojade B staining intensity in each treatment group. The distributions are significantly distinct from each other (P < 0.05, Kolmogorov–Smirnov test, a.u.: arbitrary units). Note enhanced neuronal degeneration after kainate injection, and its augmentation by glibenclamide pre-treatment.

Mentions: First, we examined changes in Kir6.1 protein levels at a later time point. After the induction of Kir6.1 transcription 1 day post- kainate injection, Kir6.1 protein levels returned to those seen in control C57BL/6 mice within 14 days (n ∇ 6–9 per group, Fig. S3), reflecting the transient nature of the induced changes. The transient transcriptional induction by kainate could be either a marker of cell damage, or a beneficial protection mechanism. Therefore, we tested basal Kir6.1 protein levels in the more resistant, namely exercised C57BL/6 or sedentary FVB/N mice. Exercise significantly enhanced Kir6.1 labelling in BG of sedentary naïve mice. Similarly, in FVB/N, the basal levels of Kir6.1 were higher compared to those of C57BL/6 mice (n ∇ 6–9, P < 0.005, Student’s t-test, Fig. 3A), Thus, higher levels of Kir6.1 protein expression in BG were correlated with improved resistance to kainate in non-injected mice.


Similar cation channels mediate protection from cerebellar exitotoxicity by exercise and inheritance.

Ben-Ari S, Ofek K, Barbash S, Meiri H, Kovalev E, Greenberg DS, Soreq H, Shoham S - J. Cell. Mol. Med. (2012)

Kir6.1 channel protects the cerebellum from kainate damage. (A) Cerebellar Kir6.1 levels. Both types of exercise (EC and TM) significantly enhanced Kir6.1 expression, and the basal Kir6.1 levels were higher in FVB/N than C57BL/6 (C57) mice (semi-quantification is based on percentage of Kir6.1 immunoreactive stained area, control value is 3.6%, *P < 0.0005, post-hoc analysis after one-way ANOVA, #P < 0.005 in comparison to sedentary C57BL/6 mice, Student’s t-test, n ∇ 6–9 per group). (B) Glibenclamide augments Kainate damage. Sagittal cerebellar slices were treated for 20 min. with either DMSO or glibenclamide (gli, 20 nM) and then with or without 20 μM kainate (30 min.). Shown are Purkinje cells stained with Flurojade B 5.5 hrs after treatment. Top: Semi-quantification is based on staining intensities normalized to background staining, as measured by Image J and control value of 95.1 arbitrary units, n ∇ 4–8 mice per treatment group, *P < 0.0005 in comparison to naïve mice, post-hoc analysis after two-way ANOVA. Bottom: Distribution histograms of Flurojade B staining intensity in each treatment group. The distributions are significantly distinct from each other (P < 0.05, Kolmogorov–Smirnov test, a.u.: arbitrary units). Note enhanced neuronal degeneration after kainate injection, and its augmentation by glibenclamide pre-treatment.
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fig03: Kir6.1 channel protects the cerebellum from kainate damage. (A) Cerebellar Kir6.1 levels. Both types of exercise (EC and TM) significantly enhanced Kir6.1 expression, and the basal Kir6.1 levels were higher in FVB/N than C57BL/6 (C57) mice (semi-quantification is based on percentage of Kir6.1 immunoreactive stained area, control value is 3.6%, *P < 0.0005, post-hoc analysis after one-way ANOVA, #P < 0.005 in comparison to sedentary C57BL/6 mice, Student’s t-test, n ∇ 6–9 per group). (B) Glibenclamide augments Kainate damage. Sagittal cerebellar slices were treated for 20 min. with either DMSO or glibenclamide (gli, 20 nM) and then with or without 20 μM kainate (30 min.). Shown are Purkinje cells stained with Flurojade B 5.5 hrs after treatment. Top: Semi-quantification is based on staining intensities normalized to background staining, as measured by Image J and control value of 95.1 arbitrary units, n ∇ 4–8 mice per treatment group, *P < 0.0005 in comparison to naïve mice, post-hoc analysis after two-way ANOVA. Bottom: Distribution histograms of Flurojade B staining intensity in each treatment group. The distributions are significantly distinct from each other (P < 0.05, Kolmogorov–Smirnov test, a.u.: arbitrary units). Note enhanced neuronal degeneration after kainate injection, and its augmentation by glibenclamide pre-treatment.
Mentions: First, we examined changes in Kir6.1 protein levels at a later time point. After the induction of Kir6.1 transcription 1 day post- kainate injection, Kir6.1 protein levels returned to those seen in control C57BL/6 mice within 14 days (n ∇ 6–9 per group, Fig. S3), reflecting the transient nature of the induced changes. The transient transcriptional induction by kainate could be either a marker of cell damage, or a beneficial protection mechanism. Therefore, we tested basal Kir6.1 protein levels in the more resistant, namely exercised C57BL/6 or sedentary FVB/N mice. Exercise significantly enhanced Kir6.1 labelling in BG of sedentary naïve mice. Similarly, in FVB/N, the basal levels of Kir6.1 were higher compared to those of C57BL/6 mice (n ∇ 6–9, P < 0.005, Student’s t-test, Fig. 3A), Thus, higher levels of Kir6.1 protein expression in BG were correlated with improved resistance to kainate in non-injected mice.

Bottom Line: Sedentary FVB/N and exercised C57BL/6 mice both expressed higher levels of these cation channels compared to sedentary C57BL/6 mice, and were both found to be less sensitive to glutamate toxicity.In addition, our findings highlight the involvement of the cholinergic anti-inflammatory pathway in insult-inducible cerebellar processes.These mechanisms are likely to play similar roles in other brain regions and injuries as well, opening new venues for targeted research efforts.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel.

Show MeSH
Related in: MedlinePlus