Dexamethasone protects against dopaminergic neurons damage in a mouse model of Parkinson's disease

Abstract

The pathological process of neurodegeneration, which is observed in Alzheimer's (AD) and Parkinson's (PD) diseases and that follows any insult to the central nervous system, is accompanied by an inflammatory reaction, which is believed to contribute to the pathogenesis of the diseases. In accordance to this, the anti-inflammatory agents are suggested to be effective in slowing or inhibiting the degenerative process. In this study, we investigated the influence of dexamethasone (DXM) on the nigrostriatal dopaminergic neurons damage following administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropiridine (MPTP). Mice C57BL received pre-treatment of the various doses of dexamethasone followed by MPTP administration (40 mg/kg). We found that dexamethasone 1 mg/kg diminished a dopamine content depletion in striatum by about 20%, when the doses of 0.1 mg/kg was ineffective and 10 mg/kg even aggravate the dopamine content decrease. In the second step of the experiment, we chose the effective doses, 1 mg/kg, and started the treatment before and 24 h after MPTP administration. We observed the same protection in both situations: less dopamine depletion and less decrease in the number of dopaminergic cells in the substantia nigra (SN). Dexamethasone also similarly decreased the inflammatory reaction (glial activation, lymphocytic infiltration) in the injured areas. Our study showed that dexamethasone may exert a neuroprotective effect towards neurons injured by MPTP, but only when used in a proper dose. The mechanism of dexamethasone protective properties may be an inhibition of inflammatory process; however, direct interactions with neurons are also possible.

Introduction

The pathological process of neurodegeneration such as is observed in Alzheimer's (AD) and Parkinson's (PD) disease is accompanied by an inflammatory reaction that is believed to contribute to the pathogenesis [1]. The inflammatory reaction consists of increasing expression and de novo synthesis of interleukins (for example IL-1β, IL-6, IL-8), as well as other cytokines and chemokines (TNFα, TGFβ, MIP-1α), complement proteins, that is associated with the activation of microglial and astroglial cells. Activated microglia cluster at the sites of injured neurons and, similar to the other tissue macrophages, express MHC class II surface glycoproteins, release the excitotoxic amino acid glutamate and produce free radicals, all of which have been proposed to have a potent neurotoxic effect. However, a secondary response to brain insult, inflammation, may cause more neuronal loss than the initial injury. In many animal models of different types of neurodegeneration, it has been shown that depression of microglial reaction may prevent neuronal death. Moreover, in AD and PD the retrospective and prospective studies have strongly suggested that anti-inflammatory treatment with conventional anti-inflammatory drugs may delay the onset or slow the progression of the disease [2], [3], [4], [5], [6].

Glucocorticoids are potent anti-inflammatory agents that act by antagonizing activatory protein-1 (AP-1) and nuclear factor-kappa B (NF-κB) promoter elements regulating transcription of inflammatory molecules [7], [8]. They inhibit the production of two enzymes involved in prostaglandin synthesis: COX-2 and phospholipase A2. Dexamethasone (DXM) treatment also reduces the production of pro-inflammatory cytokines, including interleukin-1β, and TNFα. In the brain, DXM interferes with microglial activation by inhibiting the expression of MHC class II, and downregulates microglial COX-2 and iNOS production [9]. It also inhibits microglial ramification and proliferation in vitro [10], and induces expression of microglial lipocortin that inhibits microglial activation and exert a neuroprotective effect [9]. Thus DXM is one of the more potent agents that may change the inflammatory component of the neurodegenerative process in the brain. Although a clinical trial with prednisone showed no protective effect in the treatment of Alzheimer's disease, such an absence of effect could result from too low a dose of the agent tested and of a high rate of adverse effects, which excluded many patients from the trial [11].

In this study, we investigated the influence of DXM on the degenerative process following intoxication with 1-methyl-4-phenyl-1,2,3,6-tetrahydropiridine (MPTP) in mice to test the hypothesis that inhibition of inflammation my exert a neuroprotective effect. MPTP causes the depletion of the dopamine content in striatum, a decrease in the number of the dopaminergic cells in the substantia nigra (SN), and an abundant reaction of microglia and astrocytes [12], [13]. Additionally, an increased expression of IL-1, IL-6, TNF alfa, MHC class I and II, ICAM-1 and lymphocytic infiltration was observed in the SN [14], [15], [16]. In this work, we investigated the effect of pre-treatment with different doses of DXM, as well as treatment that started 24 h after MPTP intoxication. We showed that treatment that followed toxic damage of dopaminergic neurons might also prevent neuronal degeneration and inhibit the inflammatory reaction in the impaired structures.