TY - JOUR
T1 - In vivo and in vitro effects of pilocarpine
T2 - Relevance to ictogenesis
AU - Marchi, Nicola
AU - Oby, Emily
AU - Batra, Ayush
AU - Uva, Laura
AU - De Curtis, Marco
AU - Hernandez, Nadia
AU - Van Boxel-Dezaire, Anette
AU - Najm, Imad
AU - Janigro, Damir
PY - 2007/10
Y1 - 2007/10
N2 - Objectives: A common experimental model of status epilepticus (SE) utilizes intraperitoneal administration of the cholinergic agonist pilocarpine preceded by methyl-scopolamine treatment. Currently, activation of cholinergic neurons is recognized as the only factor triggering pilocarpine SE. However, cholinergic receptors are also widely distributed systemically and pretreatment with methyl-scopolamine may not be sufficient to counteract the effects of systemically injected pilocarpine. The extent of such peripheral events and the contribution to SE are unknown and the possibility that pilocarpine also induces SE by peripheral actions is yet untested. Methods: We measured in vivo at onset of SE: brain and blood pilocarpine levels, blood-brain barrier (BBB) permeability, T-lymphocyte activation and serum levels of IL-1β and TNF-α. The effects of pilocarpine on neuronal excitability was assessed in vitro on hippocampal slices or whole guinea pig brain preparations in presence of physiologic or elevated [K+]out. Results: Pilocarpine blood and brain levels at SE were 1400 ± 200 μM and 200 ± 80 μM, respectively. In vivo, after pilocarpine injection, increased serum IL-1β, decreased CD4:CD8 T-lymphocyte ratios and focal BBB leakage were observed. In vitro, pilocarpine failed to exert significant synchronized epileptiform activity when applied at concentrations identical or higher to levels measured in vivo. Intense electrographic seizure-like events occurred only in the copresence of levels of K+ (6 mM) mimicking BBB leakage. Conclusions: Early systemic events increasing BBB permeability may promote entry of cofactors (e. g. K+) into the brain leading to pilocarpine-induced SE. Disturbance of brain homeostasis represents an etiological factor contributing to pilocarpine seizures.
AB - Objectives: A common experimental model of status epilepticus (SE) utilizes intraperitoneal administration of the cholinergic agonist pilocarpine preceded by methyl-scopolamine treatment. Currently, activation of cholinergic neurons is recognized as the only factor triggering pilocarpine SE. However, cholinergic receptors are also widely distributed systemically and pretreatment with methyl-scopolamine may not be sufficient to counteract the effects of systemically injected pilocarpine. The extent of such peripheral events and the contribution to SE are unknown and the possibility that pilocarpine also induces SE by peripheral actions is yet untested. Methods: We measured in vivo at onset of SE: brain and blood pilocarpine levels, blood-brain barrier (BBB) permeability, T-lymphocyte activation and serum levels of IL-1β and TNF-α. The effects of pilocarpine on neuronal excitability was assessed in vitro on hippocampal slices or whole guinea pig brain preparations in presence of physiologic or elevated [K+]out. Results: Pilocarpine blood and brain levels at SE were 1400 ± 200 μM and 200 ± 80 μM, respectively. In vivo, after pilocarpine injection, increased serum IL-1β, decreased CD4:CD8 T-lymphocyte ratios and focal BBB leakage were observed. In vitro, pilocarpine failed to exert significant synchronized epileptiform activity when applied at concentrations identical or higher to levels measured in vivo. Intense electrographic seizure-like events occurred only in the copresence of levels of K+ (6 mM) mimicking BBB leakage. Conclusions: Early systemic events increasing BBB permeability may promote entry of cofactors (e. g. K+) into the brain leading to pilocarpine-induced SE. Disturbance of brain homeostasis represents an etiological factor contributing to pilocarpine seizures.
KW - Blood-brain barrier
KW - Electrophysiology
KW - Inflammation
KW - Muscarinic receptors
KW - Status epilepticus
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U2 - 10.1111/j.1528-1167.2007.01185.x
DO - 10.1111/j.1528-1167.2007.01185.x
M3 - Article
C2 - 17645533
AN - SCOPUS:35148890786
SN - 0013-9580
VL - 48
SP - 1934
EP - 1946
JO - Epilepsia
JF - Epilepsia
IS - 10
ER -