DNSP-11 reduces 6-OHDA-induced caspase 3/7 activation in an SH-SY5Y cell model: Potential Role of ERK signaling pathway?

Glial cell line-derived neurotrophic factor (GDNF) has been shown to be a promising therapeutic molecule for treating Parkinson’s disease (PD). However, because of the failure of GDNF infusion in clinical trials, due to its poor bio-distribution, there was a need to develop other molecules with similar properties to GDNF that have improved bioavailability and administration. Dopamine neuron stimulating peptide-11 (DNSP-11) is a synthetic, amidated 11-amino acid neuroactive peptide derived from the human proGDNF domain. DNSP-11 has been shown to protect dopaminergic cells in vitro and restore dopaminergic activity in vivo. Therefore, the objective of our study was to test if DNSP-11 protects human dopaminergic neuroblastoma SH-SY5Y cells against 6-OHDA induced toxicity and to elucidate the protective mechanism of action. DNSP-11 reduced the 6-OHDA–induced increase in caspase-3/7 activity in SH-SY5Y cells at early time points, indicating possible protection against apoptosis. DNSP-11 also activated the cell survival signaling pathways, ERK1, 2, and 5 in SH-SY5Y cells. In addition, a single injection of DNSP-11 in adult rat striatum leads to modulation of these ERK proteins in the substantia nigra. Overall, the results indicate that DNSP-11 protects human dopaminergic neuroblastoma cells against apoptotic cell death and activates neuroprotective ERK signaling pathways, suggesting its potential therapeutic role in Parkinson’s disease (PD).