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. 2015 Jul 2:12:129.
doi: 10.1186/s12974-015-0347-z.

Increased CCL2, CCL3, CCL5, and IL-1β cytokine concentration in piriform cortex, hippocampus, and neocortex after pilocarpine-induced seizures

Gabriel M Arisi  1   2   3   4 , Maira L Foresti  5   6   7   8 , Khurshed Katki  9   10   11 , Lee A Shapiro  12   13   14
Affiliations

Increased CCL2, CCL3, CCL5, and IL-1β cytokine concentration in piriform cortex, hippocampus, and neocortex after pilocarpine-induced seizures

Gabriel M Arisi et al. J Neuroinflammation. .

Abstract

Background: Cytokines and chemokines play an important role in the neuroinflammatory response to an initial precipitating injury such as status epilepticus (SE). These signaling molecules participate in recruitment of immune cells, including brain macrophages (microglia), as well as neuroplastic changes, deterioration of damaged tissue, and epileptogenesis. This study describes the temporal and brain region pattern expression of numerous cytokines, including chemokines, after pilocarpine-induced seizures and discusses them in the larger context of their potential involvement in the changes that precede the development of epilepsy.

Findings: Adult rats received pilocarpine to induce SE and 90 min after seizure onset were treated with diazepam to mitigate seizures. Rats were subsequently deeply anesthetized and brain regions (hippocampus, piriform cortex, neocortex, and cerebellum) were freshly dissected at 2, 6, and 24 h or 5 days after seizures. Using methodology identical to our previous studies, simultaneous assay of multiple cytokines (CCL2, CCL3, CCL5, interleukin IL-1β, tumor necrosis factor (TNF-α)), and vascular endothelial growth factor (VEGF) was performed and compared to control rats. These proteins were selected based on existing evidence implicating them in the epileptogenic progression. A robust increase in CCL2 and CCL3 concentrations in the hippocampus, piriform cortex, and neocortex was observed at all time-points. The concentrations peaked with a ~200-fold increase 24 h after seizures and were two orders of magnitude greater than the significant increases observed for CCL5 and IL-1β in the same brain structures. TNF-α levels were altered in the piriform cortex and neocortex (24 h) and in the hippocampus (5 days) after SE.

Conclusions: Pilocarpine-induced status epilepticus causes a rapid increase of multiple cytokines in limbic and neocortical regions. Understanding the precise spatial and temporal pattern of cytokines and chemokine changes could provide more viable therapeutic targets to reduce, reverse, or prevent the development of epilepsy following a precipitating injury.

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Figures

Fig. 1
Fig. 1
CCL2 concentrations presented with a log scale to illustrate the magnitude of increased CCL2 relative to the other cytokines examined. An increase of 3–7 times the basal levels was observed 2 h after SE, 10–25 times the control levels 6 h after SE, and reached a peak 24 h after SE in the hippocampus, piriform cortex, and neocortex with increases of ~100-, ~200-, and ~250-fold, respectively. Five days after seizures, CCL2 concentration was still significantly elevated in the piriform cortex, hippocampus, and neocortex (*p < 0.001 in all cases). No significant alterations to CCL2 concentrations were observed in the cerebellum
Fig. 2
Fig. 2
CCL3 concentrations presented an increase of 60 times the basal levels 2 h after SE, 25 times the control levels 6 h after SE, and reached a peak 24 h after SE with a ~250-fold increase in the hippocampus, piriform cortex, and neocortex. Five days after seizures, CCL3 concentration was still significantly elevated in the piriform cortex (~50-fold), hippocampus (~250-fold), and neocortex (~100-fold; *p < 0.001 in all cases). No significant alterations were observed in the cerebellum
Fig. 3
Fig. 3
CCL5 concentrations presented a significant twofold increase in the piriform cortex, hippocampus (*p < 0.001), and neocortex (*p < 0.05) 24 h after SE. Five days after seizures, CCL5 concentration was still significantly elevated in the piriform cortex (*p < 0.05). No significant alterations were observed in the cerebellum
Fig. 4
Fig. 4
A significant increase in IL-1β concentration was observed in the piriform cortex, hippocampus, and neocortex 2 h after SE (*p < 0.05) and in the hippocampus and neocortex 6 h after SE (*p < 0.05), but not in the cerebellum. The peak concentration was observed 24 h after SE with a ~2-fold increase in the piriform cortex (*p < 0.05) and a ~2.5-fold in the neocortex (*p < 0.001) with no significant alteration in the hippocampus. Five days after seizures, IL-1β levels returned to control levels in all brain regions
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