Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder characterized by motor neuron degeneration. About 2% of cases are associated with mutations in the gene encoding the enzyme superoxide dismutase 1 (SOD1). Recent evidence indicates that motor neuron death is a non-cell-autonomous event that involves glial cells, particularly astrocytes. Recently, we reported that a subpopulation of astrocytes degenerates in the spinal cord of SOD1G93A transgenic mouse model of ALS. Mechanistic studies in cultured astrocytes revealed that such effect is mediated by the transmitter glutamate via the the activation of its inositol 1,4,5 triphosphate (IP3)-generating metabotropic receptor 5 (mGluR5). Since non-physiological formation of IP3 can prompt Ca²⁺ release from the intracellular stores and trigger cell death, we investigated the intracellular Ca²⁺ signalling that occurs downstream of mGluR5 in hSOD1G93A-expressing astrocytes. Primary astroglial cultures were prepared from spinal cord of newborn (0–24 hrs) mice. Contrary to wild-type cells, we found that stimulation of mGluR5 in hSOD1G93A-expressing astrocytes causes unusual rises in the intracellular Ca²⁺ concentrations that correlate with cell death. Based on these observations, we next screened the glioprotective effect of innovative drugs, namely cell-permeable therapeutics. These consist of peptidic effector moieties coupled to the selective intracellular peptide transporter TAT protein. We initially validated the usefulness of these molecules demonstrating that a control fluorescent peptide enters astrocytes in culture and is retained within the cells. We then tested the impact of specific intracellular peptides with anti-apoptotic properties on glutamate-treated hSOD1G93A-expressing astrocytes. We identify one molecule that rescue the aberrant Ca²⁺ signaling and protects the mutant cells.