Elsevier

Experimental Neurology

Volume 189, Issue 1, September 2004, Pages 189-196
Experimental Neurology

Electro-acupuncture stimulation protects dopaminergic neurons from inflammation-mediated damage in medial forebrain bundle-transected rats

https://doi.org/10.1016/j.expneurol.2004.05.028Get rights and content

Abstract

Through producing a variety of cytotoxic factors upon activation, microglia are believed to participate in the mediation of neurodegeneration. Intervention against microglial activation may therefore exert a neuroprotective effect. Our previous study has shown that the electro-acupuncture (EA) stimulation at 100 Hz can protect axotomized dopaminergic neurons from degeneration. To explore the underlying mechanism, the effects of 100 Hz EA stimulation on medial forebrain bundle (MFB) axotomy-induced microglial activation were investigated. Complement receptor 3 (CR3) immunohistochemical staining revealed that 24 sessions of 100 Hz EA stimulation (28 days after MFB transection) significantly inhibited the activation of microglia in the substantia nigra pars compacta (SNpc) induced by MFB transection. Moreover, 100 Hz EA stimulation obviously inhibited the upregulation of the levels of tumor necrosis factor (TNF)-α and interleukin (IL)-1β mRNA in the ventral midbrains in MFB-transected rats, as revealed by reverse transcriptase polymerase chain reaction (RT-PCR). ED1 immunohistochemical staining showed that a large number of macrophages appeared in the substantia nigra (SN) 14 days after MFB transection. The number of macrophages decreased by 47% in the rats that received 12 sessions of EA simulation after MFB transection. These data indicate that the neuroprotective role of 100 Hz EA stimulation on dopaminergic neurons in MFB-transected rats is likely to be mediated by suppressing axotomy-induced inflammatory responses. Taken together with our previous results, this study suggests that the neuroprotective effect of EA on the dopaminergic neurons may stem from the collaboration of its anti-inflammatory and neurotrophic actions.

Introduction

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Although the mechanism of neuronal degeneration has yet to be uncovered, accumulating evidence suggests that neuroinflammatory processes may account for the progressive death of dopaminergic neurons Grunblatt et al., 2001, Hunot and Hirsch, 2003. One of the major characteristics of neuroinflammation is the activation of microglia, the resident immune cells in the central nervous system (Liu et al., 2002). Large numbers of reactive microglia are predominantly found near the remaining dopaminergic neurons in the SNpc in postmortem parkinsonian brains. In addition, microglial activation is highest in those subregions most affected by neurodegenerative process (McGeer et al., 1988).

Unilateral transection of the medial forebrain bundle (MFB) is often used to set up an animal model of PD. Axotomy of the MFB produces a precisely defined lesion of nigrostriatal dopaminergic afferents, which results in degenerative changes in the dopaminergic cell bodies in the SNpc. Recent studies demonstrates that microglial activation is involved in the MFB axotomy-induced neurodegeneration Revuelta et al., 1999, Sugama et al., 2003. Activated microglia are believed to contribute to neurodegeneration through the release of cytotoxic compounds, such as proinflammatory cytokines, nitric oxide (NO), reactive oxygen intermediates, arachidonic acid and its derivatives (Streit et al., 1999). Moreover, activated microglia were transformed into brain phagocytes which ingested dopaminergic neurons in the early, and thus, reversible stage of neuronal apoptosis. Previous studies have suggested that the blockade of phagocytic activity of microglial cells may lead to neuroprotection Revuelta et al., 1999, Sugama et al., 2003.

In China, acupuncture has been employed to treat PD for many years, and accumulated data have shown promising effects of electro-acupuncture (EA) in alleviating the suffering of PD patients Cai and Hua, 1996, Cheng, 1996, Li, 2003, Liu et al., 1993, Wang, 2000, Wang et al., 1999, Zhuang and Wang, 2000. Our previous work demonstrated that EA stimulation at the frequency of 100 Hz, but not 2 or 0 Hz, protected dopaminergic neurons from degeneration following MFB axotomy (Liang et al., 2002). However, the mechanisms underlying the neuroprotective effect are still unknown. Son et al. (2002) reported that acupuncture stimulation was effective in suppressing the production of pro-inflammatory cytokines in the hypothalamus induced by lipopolysaccharide injection. We hypothesize that the neuroprotective effect of 100 Hz EA stimulation on dopaminergic neurons might be related to its anti-neuroinflammatory effect. The present study was conducted to evaluate the effects of 100 Hz EA stimulation on microglial activation and the transcription of proinflammatory cytokines in MFB-transected rats.

Section snippets

Animals and surgery

Forty-five adult female Wistar rats weighing 180–200 g were supplied by the Laboratory Animal Center, Peking University, and housed in a standard 12-h on/off light cycle with food and water ad libitum in the home cage. They were allowed to acclimate to their environment for 10 days before experiments. The rats were anesthetized with 350 mg/kg chloral hydrate and positioned in a stereotaxic apparatus (David Kopf Instruments, Tujunga, CA, U.S.A.) with the tooth bar set at −3.3 mm. MFB lesions

EA improves the survival of dopaminergic neurons after MFB axotomy

TH immunohistochemical staining was performed 28 days after MFB lesion, and the number of dopaminergic neurons in the SNpc was counted as previously described (Liang et al., 2002). In the MFB-lesioned rats, the number of TH-positive neurons on the lesioned side was about 40.68 ± 7.78% of that on the non-lesioned side. In animals that received 100 Hz EA after MFB transection, the survival rate of the TH-positive neurons was 67.76 ± 8.91%, which increased significantly compared to that of the MFB

Discussion

Our results demonstrate that microglial activation may be involved in the dopaminergic neuronal injury in MFB-transected rats. EA at 100 Hz significantly inhibits MFB axotomy-induced activation of microglia and the resultant increase in the levels of TNF-α and IL-1β mRNA. This may underlie the mechanism of neuroprotective effect of 100 Hz EA stimulation on dopaminergic neurons.

It has been well documented that neuroinflammation, characterized by microglial activation, may be involved in the

Acknowledgements

This study was supported by the National Basic Research Program of China (G1999054008) and NSFC fund (39970924). We express sincere thanks to Dr. Nicolas Bazan (Louisiana State University) and Dr. Ru-Rong Ji (Harvard Medical School) for their critical reading of the manuscript.

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