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

Neurobiol Dis. 2015 Feb:74:126-36. doi: 10.1016/j.nbd.2014.11.012. Epub 2014 Nov 28.


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.

Keywords: Amyotrophic lateral sclerosis; GDNF; GLT-1; Metabotropic glutamate receptor; Neurodegeneration; Neuroprotection; SODG93A.

MeSH terms

  • Amino Acids / pharmacology*
  • Amyotrophic Lateral Sclerosis / drug therapy*
  • Amyotrophic Lateral Sclerosis / pathology
  • Amyotrophic Lateral Sclerosis / physiopathology
  • Animals
  • Astrocytes / drug effects
  • Astrocytes / pathology
  • Astrocytes / physiology
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • Cells, Cultured
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Agonists / pharmacology*
  • Excitatory Amino Acid Transporter 2 / metabolism*
  • Glial Cell Line-Derived Neurotrophic Factor / metabolism*
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Motor Neurons / drug effects*
  • Motor Neurons / pathology
  • Motor Neurons / physiology
  • Receptors, Metabotropic Glutamate / genetics
  • Receptors, Metabotropic Glutamate / metabolism
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism
  • Superoxide Dismutase-1


  • Amino Acids
  • Bridged Bicyclo Compounds, Heterocyclic
  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Transporter 2
  • Gdnf protein, mouse
  • Glial Cell Line-Derived Neurotrophic Factor
  • LY 379268
  • Receptors, Metabotropic Glutamate
  • SOD1 protein, human
  • Slc1a2 protein, mouse
  • metabotropic glutamate receptor 2
  • metabotropic glutamate receptor 3
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1