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.