||Mevinphos (Mev) is an orgnophosphate insectide used for suicidal purposes in Taiwan; seizure and cardiovascular depression are commom syptoms observed in organophosphate-poisoned patients. The amygdala (AMG) is part of the limbic system and the basolateral nucleus of AMG (BLA) is one of the most seizure-prone brain structures. The central neucleus of AMG (CeA) is thought to play a central role in behavioral, physiological response and cardiovascular regulation. However, detailed mechanisms in Mev-induced seizure and cardiovascular depression by an action on AMG are lacking. Based on electroencephalographic (EEG) activity to indicate neuronal electrical activity and arterial blood pressure (AP) and heart rate (HR) to indicate cardiovascular responses, the present study investigated whether Mev acts on AMG to elicit seizure or cardiovascular depression. |
Microinjection of Mev into BLA of adult male Sprague-Dawley (SD) rats maintained under propofol anesthesia increased EEG activity in AMG, cortex and CA3 of hippocampus leading to seizure initiation; however AP, HR, respiration rate (RR) and the power density of low-frequency (LF) component of AP was not significantly changed. Microinjection of Mev into BLA also time-dependently increased protein level and mRNA of cytokines interleukin (IL)-12, IL-13, tumor suppressor factor alpha (TNFα) and interferon gamma (IFNγ) and cyclooxygenase (COX) activity in AMG. Microinjection of Mev into CA3 induced less seizure activity in cortex and CA3 than that induced by microinjection of Mev into BLA. In addition, microinjection Mev into CA3 did not induce seizure in AMG. These results suggest that Mev acted on BLA to initiate limbic seizures. Intraperitoneal injection of muscarinic receptor antagonist atropine (ATR), which can pass the blood-brain barrier (BBB), activator of GABAergic neurotransmission midazolam (MDZ) or antiinflaamatory agent pentoxifylline (PTX) and Lisofylline (LSF), but not muscarinic receptor antagonist atropine methyl nitrate (AMN), which can not pass BBB, inhibited Mev-induced seizure and increase of cytokines in AMG by an action on BLA. Microinjection of ATR, COX-1 inhibitor naproxen (NPX) or COX-2 inhibitor NS-398, antiserum against receptor of IL-12, IL-13, TNFα or IFNγ, but not nicotinic receptor antagonist mecamylamine (MEL), into BLA inhibited Mev-induced seizure and increase of cytokines and COX activity in AMG by an action on BLA. However, caspase 3 activity and DNA fragmentation at AMG were not changed by microinjection of Mev into BLA.
Microinjection of Mev into CeA induced a decrease in AP and RR leading to cardiovascular depression and an increase of power desity of LF, accompanied with insignificant HR and EEG activity change. Microinjection of Mev into CeA induced the time-dependently increase of caspase 3 activity and DNA fragmentation leading to apoptosis in AMG. Microinjection of ATR or caspase 3-dependent apoptosome inhibitor NS-3694, but not MEL, into CeA inhibited cardiovascular depression and the increase of caspase 3 activity and DNA fragmentation induced by Mev action on CeA. However, the levels of cytokines were not changed by Mev treatment.
Intravenous injection of Mev did not induce changes of partial pressure of oxygen, blood flow and the level of superoxide anion in AMG. In addition, microinjection of Mev into BLA or CeA did not affect the level of superoxide anion in AMG.
These results suggest that AMG mediates the initiation of seizure and cardiovascular depression induced by Mev. Furthermore, inflammation in BLA and apoptosis in CeA individually play an important role in Mev-induced seizure and cardiovascular depression.