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Restoration of axon conduction and motor deficits by therapeutic treatment with glatiramer acetate.

Moore S, Khalaj AJ, Patel R, Yoon J, Ichwan D, Hayardeny L, Tiwari-Woodruff SK - J. Neurosci. Res. (2014)

Bottom Line: These GA-induced cytokines and growth factors may have a direct effect on axon function.Therapeutic regimens were utilized based on promising prophylactic efficacy.Finally, GA improved callosal axon conduction and nodal protein organization in EAE.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, UCLA School of Medicine, Los Angeles, California.

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Therapeutic GA mitigates EAE-induced impairment in callosal conduction. A: Callosal lesions and demyelination during chronic EAE cause measurable conduction deficits. CAP responses were recorded on EAE post-immunization day 36 from coronal slices containing midline-crossing segments of the CC overlying the mid-dorsal hippocampus (Fig. 1A experiment). Typical CC CAP from normal (black), vehicle-treated EAE (red), and GA-treated EAE (blue) brains were evoked at a stimulus of 4 mA. N1 (fast conducting, myelinated component) and N2 (slow conducting, mostly non-myelinated component) CAP amplitudes decreased in the vehicle-treated EAE group. Treatment with GA during EAE brought CAP amplitudes closer to those of the normal group by improving the EAE-induced decreases in N1 and N2 CAP amplitudes. Dashed line represents CAP beyond the stimulus artifact. B,C: Quantification of N1 and N2 CAP amplitudes from brain slices of normal, vehicle-treated EAE, and GA-treated EAE groups was performed. CAP amplitudes at 2–4 mA current stimulation were compared. **P < 0.001, ANOVA, Bonferroni's multiple comparison post-test; n = 6 mice/group. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]
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fig07: Therapeutic GA mitigates EAE-induced impairment in callosal conduction. A: Callosal lesions and demyelination during chronic EAE cause measurable conduction deficits. CAP responses were recorded on EAE post-immunization day 36 from coronal slices containing midline-crossing segments of the CC overlying the mid-dorsal hippocampus (Fig. 1A experiment). Typical CC CAP from normal (black), vehicle-treated EAE (red), and GA-treated EAE (blue) brains were evoked at a stimulus of 4 mA. N1 (fast conducting, myelinated component) and N2 (slow conducting, mostly non-myelinated component) CAP amplitudes decreased in the vehicle-treated EAE group. Treatment with GA during EAE brought CAP amplitudes closer to those of the normal group by improving the EAE-induced decreases in N1 and N2 CAP amplitudes. Dashed line represents CAP beyond the stimulus artifact. B,C: Quantification of N1 and N2 CAP amplitudes from brain slices of normal, vehicle-treated EAE, and GA-treated EAE groups was performed. CAP amplitudes at 2–4 mA current stimulation were compared. **P < 0.001, ANOVA, Bonferroni's multiple comparison post-test; n = 6 mice/group. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Mentions: To assess the functional implications of and build upon the mechanistic insight achieved by cellular and structural assessments of GA-induced CNS improvements, we measured callosal axon conduction in coronal slices from vehicle-treated and therapeutic GA-treated EAE animals (subjects from Fig. 1A experiment, in which treatment was initiated on day 16). Our group has routinely studied axon conduction in brain slices by using an electrophysiological assay to measure local field potential change in response to stimulating a CAP in CC with a square wave current pulse (Crawford et al., 2009b, Patel et al., 2013A). With respect to time, the typical CAP shows two distinct voltage deflections: N1, predominantly from large myelinated axons, and N2, predominantly from smaller non-myelinated axons (Fig. 7A). During EAE, both N1 and N2 CAP amplitudes were decreased to nearly 50% of normal (P < 0.001; Fig. 7A–C). We report significantly increased N1 and N2 CAP amplitudes in GA-treated EAE CC compared with vehicle-treated EAE CC (P < 0.001; Fig. 7A–C). This indicates that GA is neuroprotective of both myelinated and non-myelinated callosal axons. Given our immunohistochemical findings, these functional improvements may be due to a combination of reduced axon loss, increased functional myelination, and reduced axon damage.


Restoration of axon conduction and motor deficits by therapeutic treatment with glatiramer acetate.

Moore S, Khalaj AJ, Patel R, Yoon J, Ichwan D, Hayardeny L, Tiwari-Woodruff SK - J. Neurosci. Res. (2014)

Therapeutic GA mitigates EAE-induced impairment in callosal conduction. A: Callosal lesions and demyelination during chronic EAE cause measurable conduction deficits. CAP responses were recorded on EAE post-immunization day 36 from coronal slices containing midline-crossing segments of the CC overlying the mid-dorsal hippocampus (Fig. 1A experiment). Typical CC CAP from normal (black), vehicle-treated EAE (red), and GA-treated EAE (blue) brains were evoked at a stimulus of 4 mA. N1 (fast conducting, myelinated component) and N2 (slow conducting, mostly non-myelinated component) CAP amplitudes decreased in the vehicle-treated EAE group. Treatment with GA during EAE brought CAP amplitudes closer to those of the normal group by improving the EAE-induced decreases in N1 and N2 CAP amplitudes. Dashed line represents CAP beyond the stimulus artifact. B,C: Quantification of N1 and N2 CAP amplitudes from brain slices of normal, vehicle-treated EAE, and GA-treated EAE groups was performed. CAP amplitudes at 2–4 mA current stimulation were compared. **P < 0.001, ANOVA, Bonferroni's multiple comparison post-test; n = 6 mice/group. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4305217&req=5

fig07: Therapeutic GA mitigates EAE-induced impairment in callosal conduction. A: Callosal lesions and demyelination during chronic EAE cause measurable conduction deficits. CAP responses were recorded on EAE post-immunization day 36 from coronal slices containing midline-crossing segments of the CC overlying the mid-dorsal hippocampus (Fig. 1A experiment). Typical CC CAP from normal (black), vehicle-treated EAE (red), and GA-treated EAE (blue) brains were evoked at a stimulus of 4 mA. N1 (fast conducting, myelinated component) and N2 (slow conducting, mostly non-myelinated component) CAP amplitudes decreased in the vehicle-treated EAE group. Treatment with GA during EAE brought CAP amplitudes closer to those of the normal group by improving the EAE-induced decreases in N1 and N2 CAP amplitudes. Dashed line represents CAP beyond the stimulus artifact. B,C: Quantification of N1 and N2 CAP amplitudes from brain slices of normal, vehicle-treated EAE, and GA-treated EAE groups was performed. CAP amplitudes at 2–4 mA current stimulation were compared. **P < 0.001, ANOVA, Bonferroni's multiple comparison post-test; n = 6 mice/group. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]
Mentions: To assess the functional implications of and build upon the mechanistic insight achieved by cellular and structural assessments of GA-induced CNS improvements, we measured callosal axon conduction in coronal slices from vehicle-treated and therapeutic GA-treated EAE animals (subjects from Fig. 1A experiment, in which treatment was initiated on day 16). Our group has routinely studied axon conduction in brain slices by using an electrophysiological assay to measure local field potential change in response to stimulating a CAP in CC with a square wave current pulse (Crawford et al., 2009b, Patel et al., 2013A). With respect to time, the typical CAP shows two distinct voltage deflections: N1, predominantly from large myelinated axons, and N2, predominantly from smaller non-myelinated axons (Fig. 7A). During EAE, both N1 and N2 CAP amplitudes were decreased to nearly 50% of normal (P < 0.001; Fig. 7A–C). We report significantly increased N1 and N2 CAP amplitudes in GA-treated EAE CC compared with vehicle-treated EAE CC (P < 0.001; Fig. 7A–C). This indicates that GA is neuroprotective of both myelinated and non-myelinated callosal axons. Given our immunohistochemical findings, these functional improvements may be due to a combination of reduced axon loss, increased functional myelination, and reduced axon damage.

Bottom Line: These GA-induced cytokines and growth factors may have a direct effect on axon function.Therapeutic regimens were utilized based on promising prophylactic efficacy.Finally, GA improved callosal axon conduction and nodal protein organization in EAE.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, UCLA School of Medicine, Los Angeles, California.

Show MeSH
Related in: MedlinePlus