2-chloro-5-hydroxyphenylglycine and Inflammation

The Group I metabotropic glutamate receptor 5 (mGluR5) can modulate addiction, pain, and neuronal cell death. Expression of some mGluRs, such as Group II and III mGluRs, has been reported in microglia and may affect their activation. However, the expression and role of mGluR5 in microglia is unclear. Using immunocytochemistry and Western blot, we demonstrate that mGluR5 protein is expressed in primary microglial cultures. Activation of mGluR5 using the selective agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) significantly reduces microglial activation in response to lipopolysaccharide, as indicated by a reduction in nitric oxide, reactive oxygen species, and TNFalpha production. Microglial induced neurotoxicity is also markedly reduced by CHPG treatment. The anti-inflammatory effects of CHPG are not observed in microglial cultures from mGluR5 knockout mice and are blocked by selective mGluR5 antagonists, suggesting that these actions are mediated by the mGluR5 receptor. Anti-inflammatory actions of mGluR5 activation are attenuated by phospholipase C and protein kinase C inhibitors, as well as by calcium chelators, suggesting that the mGluR5 activation in microglia involves the G(alphaq)-protein signal transduction pathway. These data indicate that microglial mGluR5 may represent a novel target for modulating neuroinflammation, an important component of both acute and chronic neurodegenerative disorders.

Topics: Animals; Anti-Inflammatory Agents; Calcium; Cells, Cultured; Chelating Agents; Excitatory Amino Acid Agents; Glycine; Inflammation; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Neurons; Neuroprotective Agents; Nitric Oxide; Phenylacetates; Protein Kinase C; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Tumor Necrosis Factor-alpha; Type C Phospholipases

The antinociceptive effects of honokiol and magnolol, two major bioactive constituents of the bark of Magnolia officinalis, were investigated on animal paw licking responses and thermal hyperalgesia induced by glutamate receptor agonists including glutamate, N-methyl-D-aspartate (NMDA), and metabotropic glutamate 5 receptor (mGluR5) activator (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), as well as inflammatory mediators such as substance P and prostaglandin E2 (PGE2) in mice. The actions of honokiol and magnolol on glutamate-induced c-Fos expression in the spinal cord dorsal horn were also examined. Our data showed that honokiol and magnolol blocked glutamate-, substance P- and PGE2-induced inflammatory pain with similar potency and efficacy. Consistently, honokiol and magnolol significantly decreased glutamate-induced c-Fos protein expression in superficial (I-II) laminae of the L4-L5 lumbar dorsal horn. However, honokiol was more selective than magnolol for inhibition of NMDA-induced licking behavioral and thermal hyperalgesia. In contrast, magnolol was more potent to block CHPG-mediated thermal hyperalgesia. These results demonstrate that honokiol and magnolol effectively decreased the inflammatory pain. Furthermore, their different potency on inhibition of nociception provoked by NMDA receptor and mGluR5 activation should be considered.

Topics: Analgesics; Animals; Anti-Infective Agents; Biphenyl Compounds; Dinoprostone; Excitatory Amino Acid Agents; Glycine; Immunohistochemistry; Inflammation; Lignans; Male; Mice; N-Methylaspartate; Phenylacetates; Proto-Oncogene Proteins c-fos; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate