We examined the possibility that catecholamines (CA) could act as endogenous modulators of neuronal death. Exposure to high doses (> 100 μM) of dopamine (DA) caused widespread neuronal death within 24 h in mouse cortical cell cultures and was accompanied by cell body shrinkage, aggregation and condensation of nuclear chromatin, and prominent internucleosomal DNA fragmentation. Epinephrine, but not norepinephrine (NE), was slightly toxic to neurons at doses higher than 1 mM. DA-induced death was attenuated by the addition of three different anti-apoptosis agents, 1 χ/ml cycloheximide, 25 mM K+, or 100 ng/ml brain-derived neurotrophic factor (BDNF). While treatment with 100 μM N-acetyl-L-cysteine attenuated DA neurotoxicity, neither the glutamate antagonists (10 μM MK-801 plus 50 μM CNQX) nor several antioxidants [trolox, 100 μM; Mn (III) tetrakis (4-benzoic acid) porphyrin chloride, 100 μM; Mn (III) tetrakis (1-methyl-4-pyridyl) prophyrin pentachloride, 100 μM; N-tert-butyl-α-phenylnitrone, 3 mM] prevented the CA-induced apoptosis. Interestingly, all CA at 1-30 μM attenuated free radical-mediated neuronal necrosis following exposure to 30 μM Fe2+ or 200 μM H2O2, which was insensitive to DA or NE antagonists. Like trolox, CA reduced levels of the stable free radical 1,1-diphenyl-2- picrylhydrazyl under cell-free conditions, raising the possibility that CA as an antioxidant protects neurons. We also found that the neuroprotective effect of CA prolonged the protective effects of BDNF against serum deprivation. The present findings suggest that CA induces apoptosis at high doses but prevents free radical-mediated neurotoxicity as an anti-oxidant without being coupled to the receptors.
All Science Journal Classification (ASJC) codes
- Developmental Neuroscience