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Levetiracetam Differentially Alters CD95 Expression of Neuronal Cells and the Mitochondrial Membrane Potential of Immune and Neuronal Cells in vitro.

Rogers SK, Shapiro LA, Tobin RP, Tow B, Zuzek A, Mukherjee S, Newell-Rogers MK - Front Neurol (2014)

Bottom Line: Despite its increasing popularity as a relatively safe and effective anti-convulsive treatment option, its mechanism(s) of action are poorly understood.In contrast, levetiracetam decreases the mitochondrial membrane potential of splenocytes and this effect was dependent on intact invariant chain, thus implicating immune cell interactions.These results suggest that both neuronal and non-neuronal anti-epileptic activities of levetiracetam involve control over energy metabolism, more specifically, mΔΨ.

View Article: PubMed Central - PubMed

Affiliation: Department of Anthropology, University of Texas , Austin, TX , USA.

ABSTRACT
Epilepsy is a neurological seizure disorder that affects over 100 million people worldwide. Levetiracetam, either alone, as monotherapy, or as adjunctive treatment, is widely used to control certain types of seizures. Despite its increasing popularity as a relatively safe and effective anti-convulsive treatment option, its mechanism(s) of action are poorly understood. Studies have suggested neuronal, glial, and immune mechanisms of action. Understanding the precise mechanisms of action of levetiracetam would be extremely beneficial in helping to understand the processes involved in seizure generation and epilepsy. Moreover, a full understanding of these mechanisms would help to create more efficacious treatments while minimizing side-effects. The current study examined the effects of levetiracetam on the mitochondrial membrane potential of neuronal and non-neuronal cells, in vitro, in order to determine if levetiracetam influences metabolic processes in these cell types. In addition, this study sought to address possible immune-mediated mechanisms by determining if levetiracetam alters the expression of immune receptor-ligand pairs. The results show that levetiracetam induces expression of CD95 and CD178 on NGF-treated C17.2 neuronal cells. The results also show that levetiracetam increases mitochondrial membrane potential on C17.2 neuronal cells in the presence of nerve growth factor. In contrast, levetiracetam decreases the mitochondrial membrane potential of splenocytes and this effect was dependent on intact invariant chain, thus implicating immune cell interactions. These results suggest that both neuronal and non-neuronal anti-epileptic activities of levetiracetam involve control over energy metabolism, more specifically, mΔΨ. Future studies are needed to further investigate this potential mechanism of action.

No MeSH data available.


Related in: MedlinePlus

Levetiracetam does not alter antigen processing and presentation machinery in vitro. Mean fluorescence intensity (MFI) as measure of relative expression level of (A) MHCII+ and (B) CLIP on splenocytes 48 h after treatment with or without Lev. (C) MFI Lysosensor Green as a relative measure of lysosomal acidity of splenocytes 48 h after treatment with Lev. *Denotes a p-value < 0.05.
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Figure 4: Levetiracetam does not alter antigen processing and presentation machinery in vitro. Mean fluorescence intensity (MFI) as measure of relative expression level of (A) MHCII+ and (B) CLIP on splenocytes 48 h after treatment with or without Lev. (C) MFI Lysosensor Green as a relative measure of lysosomal acidity of splenocytes 48 h after treatment with Lev. *Denotes a p-value < 0.05.

Mentions: In addition to examining neuronal cells, we also examined peripheral immune cells from the spleen. We examined numbers of T cells and numbers of MHCII+ cells (which includes macrophages and B cells), as well as CD95 expression on these cells. The results showed that levetiracetam treatment resulted in no significant effect on the number of CD3+ T cells (Figure 3A), MHCII+ (Figure 3B) cells, nor on the levels of CD95 expression by T cells (Figure 3C), and non-T cells (Figure 3D). In addition, we examined overall levels of MHCII and CLIP on non-T cells (Figures 4A,B) to address the possibility that levetiracetam alters immunogenicity of peripheral immune cells. No changes were observed for either of these variables (Figures 4A,B). To further detect levetiracetam-induced changes in processing or presentation by immune cells, we assessed lysosomal acidity and found no significant changes (Figure 4C).


Levetiracetam Differentially Alters CD95 Expression of Neuronal Cells and the Mitochondrial Membrane Potential of Immune and Neuronal Cells in vitro.

Rogers SK, Shapiro LA, Tobin RP, Tow B, Zuzek A, Mukherjee S, Newell-Rogers MK - Front Neurol (2014)

Levetiracetam does not alter antigen processing and presentation machinery in vitro. Mean fluorescence intensity (MFI) as measure of relative expression level of (A) MHCII+ and (B) CLIP on splenocytes 48 h after treatment with or without Lev. (C) MFI Lysosensor Green as a relative measure of lysosomal acidity of splenocytes 48 h after treatment with Lev. *Denotes a p-value < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3927234&req=5

Figure 4: Levetiracetam does not alter antigen processing and presentation machinery in vitro. Mean fluorescence intensity (MFI) as measure of relative expression level of (A) MHCII+ and (B) CLIP on splenocytes 48 h after treatment with or without Lev. (C) MFI Lysosensor Green as a relative measure of lysosomal acidity of splenocytes 48 h after treatment with Lev. *Denotes a p-value < 0.05.
Mentions: In addition to examining neuronal cells, we also examined peripheral immune cells from the spleen. We examined numbers of T cells and numbers of MHCII+ cells (which includes macrophages and B cells), as well as CD95 expression on these cells. The results showed that levetiracetam treatment resulted in no significant effect on the number of CD3+ T cells (Figure 3A), MHCII+ (Figure 3B) cells, nor on the levels of CD95 expression by T cells (Figure 3C), and non-T cells (Figure 3D). In addition, we examined overall levels of MHCII and CLIP on non-T cells (Figures 4A,B) to address the possibility that levetiracetam alters immunogenicity of peripheral immune cells. No changes were observed for either of these variables (Figures 4A,B). To further detect levetiracetam-induced changes in processing or presentation by immune cells, we assessed lysosomal acidity and found no significant changes (Figure 4C).

Bottom Line: Despite its increasing popularity as a relatively safe and effective anti-convulsive treatment option, its mechanism(s) of action are poorly understood.In contrast, levetiracetam decreases the mitochondrial membrane potential of splenocytes and this effect was dependent on intact invariant chain, thus implicating immune cell interactions.These results suggest that both neuronal and non-neuronal anti-epileptic activities of levetiracetam involve control over energy metabolism, more specifically, mΔΨ.

View Article: PubMed Central - PubMed

Affiliation: Department of Anthropology, University of Texas , Austin, TX , USA.

ABSTRACT
Epilepsy is a neurological seizure disorder that affects over 100 million people worldwide. Levetiracetam, either alone, as monotherapy, or as adjunctive treatment, is widely used to control certain types of seizures. Despite its increasing popularity as a relatively safe and effective anti-convulsive treatment option, its mechanism(s) of action are poorly understood. Studies have suggested neuronal, glial, and immune mechanisms of action. Understanding the precise mechanisms of action of levetiracetam would be extremely beneficial in helping to understand the processes involved in seizure generation and epilepsy. Moreover, a full understanding of these mechanisms would help to create more efficacious treatments while minimizing side-effects. The current study examined the effects of levetiracetam on the mitochondrial membrane potential of neuronal and non-neuronal cells, in vitro, in order to determine if levetiracetam influences metabolic processes in these cell types. In addition, this study sought to address possible immune-mediated mechanisms by determining if levetiracetam alters the expression of immune receptor-ligand pairs. The results show that levetiracetam induces expression of CD95 and CD178 on NGF-treated C17.2 neuronal cells. The results also show that levetiracetam increases mitochondrial membrane potential on C17.2 neuronal cells in the presence of nerve growth factor. In contrast, levetiracetam decreases the mitochondrial membrane potential of splenocytes and this effect was dependent on intact invariant chain, thus implicating immune cell interactions. These results suggest that both neuronal and non-neuronal anti-epileptic activities of levetiracetam involve control over energy metabolism, more specifically, mΔΨ. Future studies are needed to further investigate this potential mechanism of action.

No MeSH data available.


Related in: MedlinePlus