TY - JOUR
T1 - Activation of mGlu3 metabotropic glutamate receptors enhances GDNF and GLT-1 formation in the spinal cord and rescues motor neurons in the SOD-1 mouse model of amyotrophic lateral sclerosis
AU - Battaglia, Giuseppe
AU - Riozzi, Barbara
AU - Bucci, Domenico
AU - Di Menna, Luisa
AU - Molinaro, Gemma
AU - Pallottino, Simone
AU - Nicoletti, Ferdinando
AU - Bruno, Valeria
N1 - Publisher Copyright:
© 2014.
PY - 2015/2/1
Y1 - 2015/2/1
N2 - Enhancement of glial-derived neurotrophic factor (GDNF) is an established therapeutic target for amyotrophic lateral sclerosis (ALS). Activation of group II metabotropic glutamate (mGlu) receptors with the orthosteric agonist, LY379268, enhanced GDNF levels in cultured spinal cord astrocytes from wild-type mice and mGlu2-/- mice, but not in astrocytes from mGlu3-/- mice. LY379268 protected Sternberger monoclonal incorporated antibody-32 (SMI-32)+ motor neurons against excitotoxic death in mixed cultures of spinal cord cells, and its action was abrogated by anti-GDNF antibodies. Acute systemic injection of LY379268 (0.5, 1 or 5mg/kg, i.p.) enhanced spinal cord GDNF levels in wild-type and mGlu2-/- mice, but not in mGlu3-/- mice. No tolerance developed to the GDNF-enhancing effect of LY379268 when the drug was continuously delivered for 28days by means of s.c. osmotic minipumps (0.5-5mg/day). Double fluorescent immunostaining showed a co-localization of GDNF with the astrocyte marker, GFAP, but not with the neuronal marker, Neuronal Nuclear Antigen (NeuN), or with SMI-32. Continuous infusion of LY379268 also enhanced the expression of the glutamate transporter GLT-1, in the spinal cord. These data laid the groundwork for the study of LY379268 in ALS mice. Continuous treatment with 1 or 5mg/kg/day with LY379268 had a beneficial effect on neurological disability in SOD1G93A mice. At day 40 of treatment, LY379268 enhanced spinal cord levels of GDNF and GLT-1, and rescued spinal cord motor neurons, as assessed by stereologic counting of SMI-32+ cells. LY379268 had no significant effect on the mortality rate of SODG93A. These findings encourage the development of selective mGlu3 receptor agonists/enhancers as neuroprotective agents in ALS.
AB - Enhancement of glial-derived neurotrophic factor (GDNF) is an established therapeutic target for amyotrophic lateral sclerosis (ALS). Activation of group II metabotropic glutamate (mGlu) receptors with the orthosteric agonist, LY379268, enhanced GDNF levels in cultured spinal cord astrocytes from wild-type mice and mGlu2-/- mice, but not in astrocytes from mGlu3-/- mice. LY379268 protected Sternberger monoclonal incorporated antibody-32 (SMI-32)+ motor neurons against excitotoxic death in mixed cultures of spinal cord cells, and its action was abrogated by anti-GDNF antibodies. Acute systemic injection of LY379268 (0.5, 1 or 5mg/kg, i.p.) enhanced spinal cord GDNF levels in wild-type and mGlu2-/- mice, but not in mGlu3-/- mice. No tolerance developed to the GDNF-enhancing effect of LY379268 when the drug was continuously delivered for 28days by means of s.c. osmotic minipumps (0.5-5mg/day). Double fluorescent immunostaining showed a co-localization of GDNF with the astrocyte marker, GFAP, but not with the neuronal marker, Neuronal Nuclear Antigen (NeuN), or with SMI-32. Continuous infusion of LY379268 also enhanced the expression of the glutamate transporter GLT-1, in the spinal cord. These data laid the groundwork for the study of LY379268 in ALS mice. Continuous treatment with 1 or 5mg/kg/day with LY379268 had a beneficial effect on neurological disability in SOD1G93A mice. At day 40 of treatment, LY379268 enhanced spinal cord levels of GDNF and GLT-1, and rescued spinal cord motor neurons, as assessed by stereologic counting of SMI-32+ cells. LY379268 had no significant effect on the mortality rate of SODG93A. These findings encourage the development of selective mGlu3 receptor agonists/enhancers as neuroprotective agents in ALS.
KW - Amyotrophic lateral sclerosis
KW - GDNF
KW - GLT-1
KW - Metabotropic glutamate receptor
KW - Neurodegeneration
KW - Neuroprotection
KW - SODG93A
UR - http://www.scopus.com/inward/record.url?scp=84918838479&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84918838479&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2014.11.012
DO - 10.1016/j.nbd.2014.11.012
M3 - Article
C2 - 25434487
AN - SCOPUS:84918838479
SN - 0969-9961
VL - 74
SP - 126
EP - 136
JO - Neurobiology of Disease
JF - Neurobiology of Disease
ER -