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Methamphetamine-induced neuronal necrosis: the role of electrographic seizure discharges
Denson G Fujikawa1, Emil S Pais2, Ernesto R Aviles2
1Experimental Neurology Laboratory, Sepulveda VA Ambulatory Care Center and Nursing Home, VA Greater Los Angeles Healthcare System, North Hills, CA, USA; Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Abstract:
We have evidence that methamphetamine (METH)-induced neuronal death is morphologically necrotic, not apoptotic, as is currently believed, and that electrographic seizures may be responsible. We administered 40mg/kg i.p. to 12 male C57BL/6 mice and monitored EEGs continuously and rectal temperatures every 15min, keeping rectal temperatures <41.0°C. Seven of the 12 mice had repetitive electrographic seizure discharges (RESDs) and 5 did not. The RESDs were often not accompanied by behavioral signs of seizures-i.e., they were often not accompanied by clonic forelimb movements. The 7 mice with RESDs had acidophilic neurons (the H&E light-microscopic equivalent of necrotic neurons by ultrastructural examination) in all of 7 brain regions (hippocampal CA1, CA2, CA3 and hilus, amygdala, piriform cortex and entorhinal cortex), the same brain regions damaged following generalized seizures, 24h after METH administration. The 5 mice without RESDs had a few acidophilic neurons in 4 of the 7 brain regions, but those with RESDs had significantly more in 6 of the 7 brain regions. Maximum rectal temperatures were comparable in mice with and without RESDs, so that cannot explain the difference between the two groups with respect to METH-induced neuronal death. Our data show that METH-induced neuronal death is morphologically necrotic, that EEGs must be recorded to detect electrographic seizure activity in rodents without behavioral evidence of seizures, and that RESDs may be responsible for METH-induced neuronal death.
Insights
Methamphetamine (METH) causes brain cell death through necrosis, not apoptosis, linked to electrographic seizures. Continuous EEG monitoring is crucial for detecting these seizures, which drive METH neurotoxicity.
Area of Science:
- Neuroscience
- Toxicology
Background:
- Methamphetamine (METH) is a potent psychostimulant with known neurotoxic effects.
- Neuronal death following METH exposure has been traditionally considered apoptotic.
- The role of electrographic seizures in METH neurotoxicity remains under investigation.
Purpose of the Study:
- To investigate the morphological nature of METH-induced neuronal death.
- To determine if electrographic seizures are responsible for METH neurotoxicity.
- To highlight the importance of electroencephalography (EEG) in METH research.
Main Methods:
- Administration of a high dose of METH (40mg/kg) to male C57BL/6 mice.
- Continuous electroencephalogram (EEG) monitoring to detect electrographic seizure discharges (RESDs).
- Histopathological examination of brain tissue 24 hours post-METH administration to identify neuronal morphology and count acidophilic neurons.
Main Results:
- METH-induced neuronal death was morphologically necrotic, characterized by acidophilic neurons.
- Mice exhibiting RESDs showed significantly more acidophilic neurons across multiple brain regions compared to those without RESDs.
- RESDs were often not accompanied by overt behavioral seizure signs, underscoring the need for EEG monitoring.
- Core body temperature did not significantly differ between groups, ruling it out as a confounding factor.
Conclusions:
- METH-induced neuronal death is primarily necrotic, not apoptotic.
- Repetitive electrographic seizure discharges (RESDs) are strongly implicated in METH neurotoxicity.
- EEG monitoring is essential for accurately assessing METH-induced seizure activity and its consequences in preclinical studies.
