| In Parkinson's disease (PD) there is a selective loss of dopamine (DA) neurons in the substantia nigra (SN) as well as significant cell death in the locus coeruleus (LC) where norepinepbrine (NE) is produced. Many believe that the loss of NE in PD worsens the SN degeneration by increasing neuroinflammation through activation of microglia. We tested this in culture and in mice. BV-2 mouse microglial cell cultures treated with lipopolysaccharide (LPS) increased their production of tumor necrosis factor (TNF-alpha). Both alpha and beta NE agonists decreased the LPS-induced TNF-alpha increases in a dose-dependent and reversible fashion. Mice pretreated with the NE neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4 (40mg/kg)) exhibited increased DA neuron loss following treatment with 1-methyl-4-phenyl, 1,2,3,6 tetrahydropyridine (MPTP). These data suggest that NE depletion enhances DA neuron loss by increasing microglial activation and the production of TNF-alpha. |
