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Hippocampal neuro-networks and dendritic spine perturbations in epileptogenesis are attenuated by neuroprotectin d1.

Musto AE, Walker CP, Petasis NA, Bazan NG - PLoS ONE (2015)

Bottom Line: We found brief spontaneous microepileptiform activity with high amplitudes in the CA1 pyramidal and stratum radiatum in epileptogenesis.Moreover, NPD1 treatment led to a reduction in spontaneous recurrent seizures.Our results indicate that NPD1 displays neuroprotective bioactivity on the hippocampal neuronal network ensemble that mediates aberrant circuit activity during epileptogenesis.

View Article: PubMed Central - PubMed

Affiliation: Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America.

ABSTRACT

Purpose: Limbic epileptogenesis triggers molecular and cellular events that foster the establishment of aberrant neuronal networks that, in turn, contribute to temporal lobe epilepsy (TLE). Here we have examined hippocampal neuronal network activities in the pilocarpine post-status epilepticus model of limbic epileptogenesis and asked whether or not the docosahexaenoic acid (DHA)-derived lipid mediator, neuroprotectin D1 (NPD1), modulates epileptogenesis.

Methods: Status epilepticus (SE) was induced by intraperitoneal administration of pilocarpine in adult male C57BL/6 mice. To evaluate simultaneous hippocampal neuronal networks, local field potentials were recorded from multi-microelectrode arrays (silicon probe) chronically implanted in the dorsal hippocampus. NPD1 (570 μg/kg) or vehicle was administered intraperitoneally daily for five consecutive days 24 hours after termination of SE. Seizures and epileptiform activity were analyzed in freely-moving control and treated mice during epileptogenesis and epileptic periods. Then hippocampal dendritic spines were evaluated using Golgi-staining.

Results: We found brief spontaneous microepileptiform activity with high amplitudes in the CA1 pyramidal and stratum radiatum in epileptogenesis. These aberrant activities were attenuated following systemic NPD1 administration, with concomitant hippocampal dendritic spine protection. Moreover, NPD1 treatment led to a reduction in spontaneous recurrent seizures.

Conclusions: Our results indicate that NPD1 displays neuroprotective bioactivity on the hippocampal neuronal network ensemble that mediates aberrant circuit activity during epileptogenesis. Insight into the molecular signaling mediated by neuroprotective bioactivity of NPD1 on neuronal network dysfunction may contribute to the development of anti-epileptogenic therapeutic strategies.

No MeSH data available.


Related in: MedlinePlus

Administration of neuroprotectin D1 during epileptogenesis reduces spontaneous recurrent epileptic seizures.A: Representative local field potential from the CA1-pyramidal layer three weeks after status epilepticus (epilepsy) from mice treated with NPD1 or vehicle during 5 days after status epilepticus. Note that NPD1-treated mice (NPD1) display an attenuation of spontaneous hippocampal epileptic electrical activity compared with vehicle-treated mouse (vehicle). Insets (red boxes from a-d) are traces from the vehicle: (a) initial discharges, followed by (b) synchronized poly-spike activity interrupted by bursts of high frequency discharge; (c) spike waves; and (d) post-ictal phase. Other insets (red boxes from e-g) are traces from NPD1-treated mice: (e) initial discharge; (f) synchronized spikes; and (g) post-ictal phase. B: Cumulative generalized seizures (Racine’s score > stage 3) per day and cumulative probability (C) at the third week after status epileptics are reduced in NPD1-treated mice (n = 5) vs. vehicle-treated mice (n = 6). D: Total cumulative seizures per week and duration of each locomotor seizure (E) are limited in NPD1-treated mice compared with vehicle. F: NPD1-treated mice (n = 4) show a reduced number of epileptic spikes compared with vehicle-treated mice (n = 4). Bars indicate means, and error bars represent S.E.M. p = p value (two sample t-test).
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pone.0116543.g006: Administration of neuroprotectin D1 during epileptogenesis reduces spontaneous recurrent epileptic seizures.A: Representative local field potential from the CA1-pyramidal layer three weeks after status epilepticus (epilepsy) from mice treated with NPD1 or vehicle during 5 days after status epilepticus. Note that NPD1-treated mice (NPD1) display an attenuation of spontaneous hippocampal epileptic electrical activity compared with vehicle-treated mouse (vehicle). Insets (red boxes from a-d) are traces from the vehicle: (a) initial discharges, followed by (b) synchronized poly-spike activity interrupted by bursts of high frequency discharge; (c) spike waves; and (d) post-ictal phase. Other insets (red boxes from e-g) are traces from NPD1-treated mice: (e) initial discharge; (f) synchronized spikes; and (g) post-ictal phase. B: Cumulative generalized seizures (Racine’s score > stage 3) per day and cumulative probability (C) at the third week after status epileptics are reduced in NPD1-treated mice (n = 5) vs. vehicle-treated mice (n = 6). D: Total cumulative seizures per week and duration of each locomotor seizure (E) are limited in NPD1-treated mice compared with vehicle. F: NPD1-treated mice (n = 4) show a reduced number of epileptic spikes compared with vehicle-treated mice (n = 4). Bars indicate means, and error bars represent S.E.M. p = p value (two sample t-test).

Mentions: Intra-cerebral NPD1 administration reduces seizure susceptibility in a kindling mouse model [15], and the present study discloses that systemic administration of this lipid mediator, during five consecutive days after SE (see Methods), remarkably attenuated the amplitude and number of MEA (NPD1: 0.8 ± 0.28 SEM vs. Vehicle: 2.09 ± 0.15 S.E.M.; P = 0.007) (Fig. 5A, B and C) as well as their duration (NPD1: 0.7 ± 0.07 S.E.M. vs. Vehicle: 1.72 ± 0.2 S.E.M.; P = 0.013) (Fig. 5D). Also, NPD1 reduced signal power at frequencies above 200 Hz in the DG (Fig. 5E and F). Since chronic recurrent seizures are a consequence of pilocarpine-induced SE in all adult mice [27, 34, 35], the hippocampal spontaneous epileptic seizures were analyzed during a five-day period at three weeks after SE. NPD1 administration during epileptogenesis reduced the onset of, the number, and the duration of severe spontaneous seizures compared with vehicle-treated mice (Fig. 6B–E) (Racine’s score: NPD1: 1.2 ± 0.2 S.E.M. vs. Vehicle: 3.16 ± 0.6 S.E.M., P = 0.0019; Duration: NPD1: 2.74 ± 0.72 S.E.M. vs. Vehicle: 7.23 ± 0.6 S.E.M., P = 0.014; spikes: NPD1: 1.5 ± 0.86 S.E.M. vs. Vehicle: 21.93 ± 3.23 S.E.M. P = 0.009). Also, NPD1 limited the severity of the epileptic discharge from pyramidal layer by attenuating the number of spikes compared with vehicle-treated mice (Fig. 6F).


Hippocampal neuro-networks and dendritic spine perturbations in epileptogenesis are attenuated by neuroprotectin d1.

Musto AE, Walker CP, Petasis NA, Bazan NG - PLoS ONE (2015)

Administration of neuroprotectin D1 during epileptogenesis reduces spontaneous recurrent epileptic seizures.A: Representative local field potential from the CA1-pyramidal layer three weeks after status epilepticus (epilepsy) from mice treated with NPD1 or vehicle during 5 days after status epilepticus. Note that NPD1-treated mice (NPD1) display an attenuation of spontaneous hippocampal epileptic electrical activity compared with vehicle-treated mouse (vehicle). Insets (red boxes from a-d) are traces from the vehicle: (a) initial discharges, followed by (b) synchronized poly-spike activity interrupted by bursts of high frequency discharge; (c) spike waves; and (d) post-ictal phase. Other insets (red boxes from e-g) are traces from NPD1-treated mice: (e) initial discharge; (f) synchronized spikes; and (g) post-ictal phase. B: Cumulative generalized seizures (Racine’s score > stage 3) per day and cumulative probability (C) at the third week after status epileptics are reduced in NPD1-treated mice (n = 5) vs. vehicle-treated mice (n = 6). D: Total cumulative seizures per week and duration of each locomotor seizure (E) are limited in NPD1-treated mice compared with vehicle. F: NPD1-treated mice (n = 4) show a reduced number of epileptic spikes compared with vehicle-treated mice (n = 4). Bars indicate means, and error bars represent S.E.M. p = p value (two sample t-test).
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4305283&req=5

pone.0116543.g006: Administration of neuroprotectin D1 during epileptogenesis reduces spontaneous recurrent epileptic seizures.A: Representative local field potential from the CA1-pyramidal layer three weeks after status epilepticus (epilepsy) from mice treated with NPD1 or vehicle during 5 days after status epilepticus. Note that NPD1-treated mice (NPD1) display an attenuation of spontaneous hippocampal epileptic electrical activity compared with vehicle-treated mouse (vehicle). Insets (red boxes from a-d) are traces from the vehicle: (a) initial discharges, followed by (b) synchronized poly-spike activity interrupted by bursts of high frequency discharge; (c) spike waves; and (d) post-ictal phase. Other insets (red boxes from e-g) are traces from NPD1-treated mice: (e) initial discharge; (f) synchronized spikes; and (g) post-ictal phase. B: Cumulative generalized seizures (Racine’s score > stage 3) per day and cumulative probability (C) at the third week after status epileptics are reduced in NPD1-treated mice (n = 5) vs. vehicle-treated mice (n = 6). D: Total cumulative seizures per week and duration of each locomotor seizure (E) are limited in NPD1-treated mice compared with vehicle. F: NPD1-treated mice (n = 4) show a reduced number of epileptic spikes compared with vehicle-treated mice (n = 4). Bars indicate means, and error bars represent S.E.M. p = p value (two sample t-test).
Mentions: Intra-cerebral NPD1 administration reduces seizure susceptibility in a kindling mouse model [15], and the present study discloses that systemic administration of this lipid mediator, during five consecutive days after SE (see Methods), remarkably attenuated the amplitude and number of MEA (NPD1: 0.8 ± 0.28 SEM vs. Vehicle: 2.09 ± 0.15 S.E.M.; P = 0.007) (Fig. 5A, B and C) as well as their duration (NPD1: 0.7 ± 0.07 S.E.M. vs. Vehicle: 1.72 ± 0.2 S.E.M.; P = 0.013) (Fig. 5D). Also, NPD1 reduced signal power at frequencies above 200 Hz in the DG (Fig. 5E and F). Since chronic recurrent seizures are a consequence of pilocarpine-induced SE in all adult mice [27, 34, 35], the hippocampal spontaneous epileptic seizures were analyzed during a five-day period at three weeks after SE. NPD1 administration during epileptogenesis reduced the onset of, the number, and the duration of severe spontaneous seizures compared with vehicle-treated mice (Fig. 6B–E) (Racine’s score: NPD1: 1.2 ± 0.2 S.E.M. vs. Vehicle: 3.16 ± 0.6 S.E.M., P = 0.0019; Duration: NPD1: 2.74 ± 0.72 S.E.M. vs. Vehicle: 7.23 ± 0.6 S.E.M., P = 0.014; spikes: NPD1: 1.5 ± 0.86 S.E.M. vs. Vehicle: 21.93 ± 3.23 S.E.M. P = 0.009). Also, NPD1 limited the severity of the epileptic discharge from pyramidal layer by attenuating the number of spikes compared with vehicle-treated mice (Fig. 6F).

Bottom Line: We found brief spontaneous microepileptiform activity with high amplitudes in the CA1 pyramidal and stratum radiatum in epileptogenesis.Moreover, NPD1 treatment led to a reduction in spontaneous recurrent seizures.Our results indicate that NPD1 displays neuroprotective bioactivity on the hippocampal neuronal network ensemble that mediates aberrant circuit activity during epileptogenesis.

View Article: PubMed Central - PubMed

Affiliation: Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America.

ABSTRACT

Purpose: Limbic epileptogenesis triggers molecular and cellular events that foster the establishment of aberrant neuronal networks that, in turn, contribute to temporal lobe epilepsy (TLE). Here we have examined hippocampal neuronal network activities in the pilocarpine post-status epilepticus model of limbic epileptogenesis and asked whether or not the docosahexaenoic acid (DHA)-derived lipid mediator, neuroprotectin D1 (NPD1), modulates epileptogenesis.

Methods: Status epilepticus (SE) was induced by intraperitoneal administration of pilocarpine in adult male C57BL/6 mice. To evaluate simultaneous hippocampal neuronal networks, local field potentials were recorded from multi-microelectrode arrays (silicon probe) chronically implanted in the dorsal hippocampus. NPD1 (570 μg/kg) or vehicle was administered intraperitoneally daily for five consecutive days 24 hours after termination of SE. Seizures and epileptiform activity were analyzed in freely-moving control and treated mice during epileptogenesis and epileptic periods. Then hippocampal dendritic spines were evaluated using Golgi-staining.

Results: We found brief spontaneous microepileptiform activity with high amplitudes in the CA1 pyramidal and stratum radiatum in epileptogenesis. These aberrant activities were attenuated following systemic NPD1 administration, with concomitant hippocampal dendritic spine protection. Moreover, NPD1 treatment led to a reduction in spontaneous recurrent seizures.

Conclusions: Our results indicate that NPD1 displays neuroprotective bioactivity on the hippocampal neuronal network ensemble that mediates aberrant circuit activity during epileptogenesis. Insight into the molecular signaling mediated by neuroprotective bioactivity of NPD1 on neuronal network dysfunction may contribute to the development of anti-epileptogenic therapeutic strategies.

No MeSH data available.


Related in: MedlinePlus