George R. Breese

Inflammation is implicated in the progressive nature of neurodegenerative diseases, such as Parkinson's disease, but the mechanisms are poorly understood. A single systemic lipopolysaccharide (LPS, 5 mg/kg, i.p.) or tumor necrosis factor alpha (TNFalpha, 0.25 mg/kg, i.p.) injection was administered in adult wild-type mice and in mice lacking TNFalpha receptors (TNF R1/R2(-/-)) to discern the mechanisms of inflammation transfer from the periphery to the brain and the neurodegenerative consequences. Systemic LPS administration resulted in rapid brain TNFalpha increase that remained elevated for 10 months, while peripheral TNFalpha (serum and liver) had subsided by 9 h (serum) and 1 week (liver). Systemic TNFalpha and LPS administration activated microglia and increased expression of brain pro-inflammatory factors (i.e., TNFalpha, MCP-1, IL-1beta, and NF-kappaB p65) in wild-type mice, but not in TNF R1/R2(-/-) mice. Further, LPS reduced the number of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra (SN) by 23% at 7-months post-treatment, which progressed to 47% at 10 months. Together, these data demonstrate that through TNFalpha, peripheral inflammation in adult animals can: (1) activate brain microglia to produce chronically elevated pro-inflammatory factors; (2) induce delayed and progressive loss of DA neurons in the SN. These findings provide valuable insight into the potential pathogenesis and self-propelling nature of Parkinson's disease.

1. After intracisternal administration, 6-hydroxydopamine had a greater effect on brain noradrenaline than on dopamine.2. Administration of two doses of 6-hydroxydopamine increased the depletion of noradrenaline but not of dopamine.3. Small doses of 6-hydroxydopamine decreased the concentration of noradrenaline with little or no effect on dopamine. Tyrosine hydroxylase activity was not reduced with these treatments.4. While pargyline pretreatment offered no advantage in the depletion of brain noradrenaline after 6-hydroxydopamine, depletion of brain dopamine was greatly potentiated by this treatment. The reduction of striatal tyrosine hydroxylase activity observed after 6-hydroxydopamine was also potentiated by pargyline pretreatment.5. The amounts of labelled noradrenaline and dopamine formed from (3)H-tyrosine were greatly reduced by 6-hydroxydopamine treatment. After (3)H-DOPA, formation of noradrenaline was greatly reduced while formation of labelled dopamine was only moderately reduced suggesting that decarboxylation of DOPA can occur in other than catecholamine containing neurones.6. Desmethylimipramine and imipramine inhibited depletion of noradrenaline produced by 6-hydroxydopamine but did not alter depletion of dopamine. Reserpine did not inhibit depletion of catecholamines produced by 6-hydroxydopamine.7. Administration of 6-hydroxydopamine to developing rats lowered both noradrenaline and dopamine concentrations as well as the tyrosine hydroxylase activity in the brains of these animals.

After the intracisternal administration of 6-hydroxydopamine, brain levels of norepinephrine were reduced significantly with or without pargyline pretreatment. Depletion of dopamine in the central nervous system was found to be enhanced markedly by pargyline administration at higher dose levels of 6-hydroxydopamine. Brain serotonin concentrations were not altered. The effects of 6-hydroxydopamine were long-lasting with the depletion of brain amines persisting at 78 days. After norepinephrine-H3 intracisternally to animals treated with 6-hydroxydopamine, labeled norepinephrine uptake was diminished with a corresponding reduction of deaminated catechols and a marked increased in methylated amines. Tyrosine hydroxylase activity was found to be reduced in brainstem, caudate nucleus and whole brain in 6-hydroxydopamine-treated animals. Conversion of tyrosine-H3 to labeled norepinephrine and dopamine was also markedly diminished. The results support the view that 6-hydroxydopamine produces a "central sympathectomy" when introduced into cerebrospinal fluid.