Limits...
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

Changes in mitochondrial membrane potential following treatment with levetiracetam. (A) Mean fluorescence intensity (MFI) of Mitotracker Red as a measure of relative mitochondrial membrane potential in C17.2 cells at 48 h post treatment with NGF with or without levetiracetam (Lev). (B) MFI Mitotracker Red in C57BL/6 splenocytes 48 h after treatment with or without 0.15 mM Lev. (C) MFI Mitotracker Red in in IiDef splenocytes 48 h after treatment with or without 0.15 mM Lev. (D) Table depicting percent change from NGF treatment alone, compared to NGF treatment in the presence of doses of levetiracetam. *Denotes a p-value < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3927234&req=5

Figure 1: Changes in mitochondrial membrane potential following treatment with levetiracetam. (A) Mean fluorescence intensity (MFI) of Mitotracker Red as a measure of relative mitochondrial membrane potential in C17.2 cells at 48 h post treatment with NGF with or without levetiracetam (Lev). (B) MFI Mitotracker Red in C57BL/6 splenocytes 48 h after treatment with or without 0.15 mM Lev. (C) MFI Mitotracker Red in in IiDef splenocytes 48 h after treatment with or without 0.15 mM Lev. (D) Table depicting percent change from NGF treatment alone, compared to NGF treatment in the presence of doses of levetiracetam. *Denotes a p-value < 0.05.

Mentions: Previous studies have indicated mitochondrial differences in the presence of levetiracetam (6, 7). Therefore, we determined if these differences were specific for neuronal or immune cells. Analysis of mΔΨ in C17.2 cells revealed no significant differences in the absence of NGF (Figure 1A). In the presence of NGF, levetiracetam resulted in a significant increase (Figure 1A) in mΔΨ at all concentrations tested (1.5 μm. p < 0.03; 15 μm, p < 0.05; 0.15 mM, p < 0.04; 1.5 mM, NS). It is pertinent to note that treatment with levetiracetam did not cause any observable alterations to the morphology of the C17.2 cells, either with or without NGF (data not shown). In contrast to the increased mΔΨ in the presence of NGF and levetiracetam, the impact of levetiracetam on spleen cells (Figure 1B) was a significant reduction in mΔΨ (p < 0.007). This reduction appeared to be invariant chain dependent, as splenocytes from mice deficient in invariant chain showed no significant changes in mΔΨ in response to levetiracetam (Figures 1C,D).


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)

Changes in mitochondrial membrane potential following treatment with levetiracetam. (A) Mean fluorescence intensity (MFI) of Mitotracker Red as a measure of relative mitochondrial membrane potential in C17.2 cells at 48 h post treatment with NGF with or without levetiracetam (Lev). (B) MFI Mitotracker Red in C57BL/6 splenocytes 48 h after treatment with or without 0.15 mM Lev. (C) MFI Mitotracker Red in in IiDef splenocytes 48 h after treatment with or without 0.15 mM Lev. (D) Table depicting percent change from NGF treatment alone, compared to NGF treatment in the presence of doses of levetiracetam. *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 1: Changes in mitochondrial membrane potential following treatment with levetiracetam. (A) Mean fluorescence intensity (MFI) of Mitotracker Red as a measure of relative mitochondrial membrane potential in C17.2 cells at 48 h post treatment with NGF with or without levetiracetam (Lev). (B) MFI Mitotracker Red in C57BL/6 splenocytes 48 h after treatment with or without 0.15 mM Lev. (C) MFI Mitotracker Red in in IiDef splenocytes 48 h after treatment with or without 0.15 mM Lev. (D) Table depicting percent change from NGF treatment alone, compared to NGF treatment in the presence of doses of levetiracetam. *Denotes a p-value < 0.05.
Mentions: Previous studies have indicated mitochondrial differences in the presence of levetiracetam (6, 7). Therefore, we determined if these differences were specific for neuronal or immune cells. Analysis of mΔΨ in C17.2 cells revealed no significant differences in the absence of NGF (Figure 1A). In the presence of NGF, levetiracetam resulted in a significant increase (Figure 1A) in mΔΨ at all concentrations tested (1.5 μm. p < 0.03; 15 μm, p < 0.05; 0.15 mM, p < 0.04; 1.5 mM, NS). It is pertinent to note that treatment with levetiracetam did not cause any observable alterations to the morphology of the C17.2 cells, either with or without NGF (data not shown). In contrast to the increased mΔΨ in the presence of NGF and levetiracetam, the impact of levetiracetam on spleen cells (Figure 1B) was a significant reduction in mΔΨ (p < 0.007). This reduction appeared to be invariant chain dependent, as splenocytes from mice deficient in invariant chain showed no significant changes in mΔΨ in response to levetiracetam (Figures 1C,D).

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