Abstract
Recent studies show a key role of brain inflammation in epilepsy. However, the mechanisms controlling brain immune response are only partly understood. In the periphery, acetylcholine (ACh) release by the vagus nerve restrains inflammation by inhibiting the activation of leukocytes. Recent reports suggested a similar anti-inflammatory effect for ACh in the brain. Since brain cholinergic dysfunctions are documented in epileptic animals, we explored changes in brain cholinergic gene expression and associated immune response during pilocarpine-induced epileptogenesis. Levels of acetylcholinesterase (AChE) and inflammatory markers were measured using real-time RT-PCR, in-situ hybridization and immunostaining in wild type (WT) and transgenic mice over-expressing the “synaptic” splice variant AChE-S (TgS). One month following pilocarpine, mice were video-monitored for spontaneous seizures. To test directly the effect of ACh on the brain's innate immune response, cytokines expression levels were measured in acute brain slices treated with cholinergic agents. We report a robust up-regulation of AChE as early as 48 h following pilocarpine-induced status epilepticus (SE). AChE was expressed in hippocampal neurons, microglia, and endothelial cells but rarely in astrocytes. TgS mice overexpressing AChE showed constitutive increased microglial activation, elevated levels of pro-inflammatory cytokines 48 h after SE and accelerated epileptogenesis compared to their WT counterparts. Finally we show a direct, muscarine-receptor dependant, nicotine-receptor independent anti-inflammatory effect of ACh in brain slices maintained ex vivo. Our work demonstrates for the first time, that ACh directly suppresses brain innate immune response and that AChE up-regulation after SE is associated with enhanced immune response, facilitating the epileptogenic process. Our results highlight the cholinergic system as a potential new target for the prevention of seizures and epilepsy.
Highlights
Accumulating experimental evidence indicates that brain immune response and inflammatory mediators decrease the threshold for individual seizures and contributes to the process of epileptogenesis
AChE IS UP-REGULATED DURING EPILEPTOGENESIS As previous studies showed AChE upregulation in chronic epileptic animals, we studied AChE expression 48 h after status epilepticus (SE) to challenge the hypothesis that cholinergic imbalance occurs early during the epileptogenesis process
In this study we offer experimental evidence indicating that (1) cholinergic imbalance due to upregulation of AChE within the hippocampus is associated with a local immune response; (2) such imbalance and the associated inflammation following SE is associated with epileptogenesis; and (3) ACh acts directly as a modulator of brain innate immune response and thereby affect epileptogenesis
Summary
Accumulating experimental evidence indicates that brain immune response and inflammatory mediators decrease the threshold for individual seizures and contributes to the process of epileptogenesis (for review see: Vezzani and Granata, 2005; Rijkers et al, 2009; Vezzani et al, 2011). Peripheral inflammation is controlled, amongst others, by the cholinergic anti-inflammatory pathway which involves inhibition of innate immune responses by ACh released from the vagus nerve. This mechanism is dependent on the alpha subunit of the nicotinic acetylcholine receptor (α7nAChR), which inhibits NF-kappaB nuclear translocation and suppresses cytokine release by monocytes and macrophages (Tracey, 2002, 2009). AChE inhibitors have been shown to reduce glial activation and inflammatory cytokine production in experimental autoimmune encephalomyelitis (Nizri et al, 2008) and in a cerebral hypoperfusion model in the rat (Wang et al, 2010)
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