Abstract
Neuroinflammation is implicated for dopaminergic neurodegeneration. Sulfur compounds extracted from garlic have been shown to have anti-inflammatory properties. Previously, we have investigated that thiacremonone, a sulfur compound isolated from garlic has anti-inflammatory effects on several inflammatory disease models. To investigate the protective effect of thiacremonone against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral impairment and dopaminergic neurodegeneration, 8 week old ICR mice were given thiacremonone (10 mg/kg) in drinking water for 1 month and received intraperitoneal injection of MPTP (15 mg/kg, four times with 2 h interval) during the last 7 days of treatment. Our data showed that thiacremonone decreased MPTP-induced behavioral impairments (Rotarod test, Pole test, and Gait test), dopamine depletion and microglia and astrocytes activations as well as neuroinflammation. Higher activation of p38 was found in the substantia nigra and striatum after MPTP injection, but p38 activation was reduced in thiacremonone treated group. In an in vitro study, thiacremonone (1, 2, and 5 μg/ml) effectively decreased MPP+ (0.5 mM)-induced glial activation, inflammatory mediators generation and dopaminergic neurodegeneration in cultured astrocytes and microglial BV-2 cells. Moreover, treatment of p38 MAPK inhibitor SB203580 (10 μM) further inhibited thiacremonone induced reduction of neurodegeneration and neuroinflammation. These results indicated that the anti-inflammatory compound, thiacremonone, inhibited neuroinflammation and dopaminergic neurodegeneration through inhibition of p38 activation.
Highlights
Parkinson’s disease (PD) is pathologically characterized by consequent depletion of dopamine in the striatum and dopaminergic neurodegeneration in the substantia nigra [1]
The decrement of latency was significantly lower in thiacremononetreated mice (48.3 ± 4.25 s) compared to MPTP-treated mice (36.2 ± 3.24 s) (Figure 1A)
The time to descend was significantly delayed by MPTP injection, but the delay of time was significantly less in thiacremonone-treated mice (9.7 ± 0.88 s) compared to MPTP-treated mice (10.96 ± 0.98 s) (Figure 1B)
Summary
Parkinson’s disease (PD) is pathologically characterized by consequent depletion of dopamine in the striatum and dopaminergic neurodegeneration in the substantia nigra [1]. A significant loss of dopaminergic neurons and subsequent striatal dopamine [2] are necessary before symptoms occur, resulting in a clinical diagnosis of the disorder. The 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP) animal model has been the most commonly used for inducing PD, because MPTP is a well-known dopaminergic neurotoxin [3] and causes a loss of the nigrostriatal dopaminergic neuron [4] in humans. MPTP enters into the astrocytes and metabolizes to MPP+ (active metabolite) by monoamine oxidase B (MAO B). Many studies already reported that neuroinflammation can be caused by activation of astrocytes through increased pro-inflammatory cytokines such as TNF-α and IL-1β [8, 9]. A recent study indicated that neuroinflammation is involved in the degeneration of dopaminergic neurons in PD associated animal models [10]
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