Recently, matrix metalloproteinases (MMPs) are emerging as important molecules in neuroinflammation as well as neuronal cell death. However, the role of MMPs in activated microglia remains unclear. In the present study, we found that expressions of MMP‐1, ‐3, ‐8 and ‐9 were significantly induced by single or combined treatment of immunostimulants lipopolysaccharide (LPS) or phorbol myristate acetate (PMA) in primary cultured microglia and BV2 microglial cells. Inhibition of MMP‐3 or ‐9 significantly suppressed the expression of iNOS and pro‐inflammatory cytokines and the activities of NF‐κB, AP‐1, and MAPK in LPS‐stimulated microglia. The results suggest that MMP‐3 and ‐9 both mediate LPS‐induced inflammatory reactions. Inhibition of reactive oxygen species (ROS) by N‐acetyl‐cysteine or diphenylene iodonium significantly suppressed the expression of MMP‐3, MMP‐9, NO and TNF‐α in LPS‐stimulated microglia, suggesting that ROS is an early signaling inducer in LPS‐stimulated microglial cells. MMP inhibitors also suppressed ROS production, suggesting a cross‐talk between ROS and MMPs. Collectively, the present study demonstrates that MMP‐3 and MMP‐9 play a role as inflammatory mediators in activated microglia. Pharmacological intervention of MMPs especially MMP‐3 and ‐9 would be a therapeutic strategy for the treatment of inflammatory diseases in the CNS caused by over‐activation of microglial cells.

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We investigated the neuroprotective property of analogs of dextromethorphan (DM) in lipopolysaccharide (LPS) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) models to identify neuroprotective drugs for Parkinson's disease (PD).In vivo studies showed that daily injections with DM analogs protected dopamine (DA) neurons in substantia nigra pars compacta and restored DA levels in striatum using two different models for PD. Of the five analogs studied, 3-hydroxymorphinan (3-HM), a metabolite of DM, was the most potent, and restored DA neuronal loss and DA depletion up to 90% of the controls. Behavioral studies showed an excellent correlation between potency for preventing toxin-induced decrease in motor activities and neuroprotective effects among the DM analogs studied, of which 3-HM was the most potent in attenuating behavioral damage. In vitro studies revealed two glia-dependent mechanisms for the neuroprotection by 3-HM. First, astroglia mediated the 3-HM-induced neurotrophic effect by increasing the gene expression of neurotrophic factors, which was associated with the increased acetylation of histone H3. Second, microglia participated in 3-HM-mediated neuroprotection by reducing MPTP-elicited reactive microgliosis as evidenced by the decreased production of reactive oxygen species. In summary, we show the potent neuroprotection by 3-HM in LPS and MPTP PD models investigated. With its high efficacy and low toxicity, 3-HM may be a novel therapy for PD. Parkinson's disease (pd) is a neurodegenerative disorder characterized by a chronic and progressive loss of dopamine (DA) neurons in substantia nigra pars compacta (SNpc), leading to movement disorders including dyskinesia, resting tremor, rigidity, and gait disturbance (1). Despite significant advances in understanding the pathological changes in PD, the etiology and the underlying mechanism responsible for the progressive nature of neurodegeneration remain poorly understood. Furthermore, current therapies are limited to relieving PD symptoms and are largely ineffective in halting the process of neurodegeneration. We have reported that dextromethorphan (DM), a widely used anticough agent, protected DA neurons against inflammagen LPS in midbrain neuron-glia cultures (2) and neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-elicited neurotoxicity in vivo (3) via an anti-inflammatory effect by preventing the over-activation of microglia. Furthermore, we recently reported that 3-hydroxymorphinan (3-HM), a metabolite of DM, exerted a more potent neuroprotection than DM against LPS-induced DA neurotoxicity in primary midbrain mixed neuron-glia cultures (4). We attribute the higher potency of 3-HM to its additional neurotrophic effect provided by astroglia