TY - JOUR
T1 - Activation of group III metabotropic glutamate receptors inhibits the production of RANTES in glial cell cultures
AU - Besong, Gilbert
AU - Battaglia, Giuseppe
AU - D'Onofrio, Mara
AU - Di Marco, Roberto
AU - Ngomba, Richard Teke
AU - Storto, Marianna
AU - Castiglione, Marzia
AU - Mangano, Katia
AU - Busceti, Carla L.
AU - Nicoletti, Ferdinando R.
AU - Bacon, Kevin
AU - Tusche, Michael
AU - Valenti, Ornella
AU - Conn, Peter Jeffrey
AU - Bruno, Valeria
AU - Nicoletti, Ferdinando
PY - 2002/7/1
Y1 - 2002/7/1
N2 - The chemokine RANTES is critically involved in neuroinflammation and has been implicated in the pathophysiology of multiple sclerosis. We examined the possibility that activation of G-protein-coupled metabotropic glutamate (mGlu) receptors regulates the formation of RANTES in glial cells. A 15 hr exposure of cultured astrocytes to tumor necrosis factor-α and interferon-γ induced a substantial increase in both RANTES mRNA and extracellular RANTES levels. These increases were markedly reduced when astrocytes were coincubated with L-2-amino-4-phosphono-butanoate (L-AP-4), 4-phosphonophenylglycine, or L-serine-O-phosphate, which selectively activate group III mGlu receptor subtypes (i.e., mGlu4, -6, -7, and -8 receptors). Agonists of mGlu1/5 or mGlu2/3 receptors were virtually inactive. Inhibition of RANTES release produced by L-AP-4 was attenuated by the selective group III mGlu receptor antagonist (R,S)-α-methylserine-O-phosphate or by pretreatment of the cultures with pertussis toxin. Cultured astrocytes expressed mGlu4 receptors, and the ability of L-AP-4 to inhibit RANTES release was markedly reduced in cultures prepared from mGlu4 knock-out mice. This suggests that activation of mGlu4 receptors negatively modulates the production of RANTES in glial cells. We also examined the effect of L-AP-4 on the development of experimental allergic encephalomyelitis (EAE) in Lewis rats. L-AP-4 was subcutaneously infused for 28 d by an osmotic minipump that released 250 nl/hr of a solution of 250 mM of the drug. Detectable levels of L-AP-4 (∼100 nM) were found in the brain dialysate of EAE rats. Infusion of L-AP-4 did not affect the time at onset and the severity of neurological symptoms but significantly increased the rate of recovery from EAE. In addition, lower levels of RANTES mRNA were found in the cerebellum and spinal cord of EAE rats infused with L-AP-4. These results suggest that pharmacological activation of group III mGlu receptors may be useful in the experimental treatment of neuroinflammatory CNS disorders.
AB - The chemokine RANTES is critically involved in neuroinflammation and has been implicated in the pathophysiology of multiple sclerosis. We examined the possibility that activation of G-protein-coupled metabotropic glutamate (mGlu) receptors regulates the formation of RANTES in glial cells. A 15 hr exposure of cultured astrocytes to tumor necrosis factor-α and interferon-γ induced a substantial increase in both RANTES mRNA and extracellular RANTES levels. These increases were markedly reduced when astrocytes were coincubated with L-2-amino-4-phosphono-butanoate (L-AP-4), 4-phosphonophenylglycine, or L-serine-O-phosphate, which selectively activate group III mGlu receptor subtypes (i.e., mGlu4, -6, -7, and -8 receptors). Agonists of mGlu1/5 or mGlu2/3 receptors were virtually inactive. Inhibition of RANTES release produced by L-AP-4 was attenuated by the selective group III mGlu receptor antagonist (R,S)-α-methylserine-O-phosphate or by pretreatment of the cultures with pertussis toxin. Cultured astrocytes expressed mGlu4 receptors, and the ability of L-AP-4 to inhibit RANTES release was markedly reduced in cultures prepared from mGlu4 knock-out mice. This suggests that activation of mGlu4 receptors negatively modulates the production of RANTES in glial cells. We also examined the effect of L-AP-4 on the development of experimental allergic encephalomyelitis (EAE) in Lewis rats. L-AP-4 was subcutaneously infused for 28 d by an osmotic minipump that released 250 nl/hr of a solution of 250 mM of the drug. Detectable levels of L-AP-4 (∼100 nM) were found in the brain dialysate of EAE rats. Infusion of L-AP-4 did not affect the time at onset and the severity of neurological symptoms but significantly increased the rate of recovery from EAE. In addition, lower levels of RANTES mRNA were found in the cerebellum and spinal cord of EAE rats infused with L-AP-4. These results suggest that pharmacological activation of group III mGlu receptors may be useful in the experimental treatment of neuroinflammatory CNS disorders.
KW - Chemokines
KW - Experimental allergic encephalomyelitis
KW - Glial cultures
KW - Leukocytes
KW - mGlu4 receptor
KW - Multiple sclerosis
UR - http://www.scopus.com/inward/record.url?scp=0036662772&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036662772&partnerID=8YFLogxK
M3 - Article
C2 - 12097492
AN - SCOPUS:0036662772
VL - 22
SP - 5403
EP - 5411
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 13
ER -