Salsolinol, an Endogenous Compound Triggers a Two-Phase Opposing Action in the Central Nervous System

Salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline), an endogenous compound present in the brain, was suspected of participation in the etiopathogenesis of Parkinson’s disease, the most common serious movement disorder worldwide. In this study, we evaluated the effect of different (50, 100, and 500 µM) concentrations of salsolinol on markers of glutamate-induced apoptotic and neurotoxic cell damage, such as caspase-3 activity, lactate dehydrogenase (LDH) release, and the loss of mitochondrial membrane potential. Biochemical data were complemented with the cellular analysis, including Hoechst 33342 and calcein AM staining, to visualize apoptotic DNA-fragmentation and to assess cell survival, respectively. The assessment of all investigated parameters was performed in primary cultures of rat or mouse hippocampal and striatum cells. Our study showed that salsolinol had biphasic effects, namely, at lower concentrations (50 and 100 µM), it demonstrated a distinct neuroprotective activity, whereas in the highest one (500 µM) caused neurotoxic effect. Salsolinol in concentrations of 50 and 100 µM significantly antagonized the pro-apoptotic and neurotoxic effects caused by 1 mM glutamate. Salsolinol diminished the number of bright fragmented nuclei with condensed chromatin and increased cell survival in Hoechst 33342 and calcein AM staining in hippocampal cultures. Additionally, in the low 50 µM concentration, it produced a significant inhibition of glutamate-induced loss of membrane mitochondrial potential. Only the highest concentration of salsolinol (500 µM) enhanced the glutamate excitotoxicity. Ex vivo studies indicated that both acute and chronic administration of salsolinol did not affect the dopamine metabolism, its striatal concentration or α-synuclein and tyrosine hydroxylase protein level in the rat substantia nigra and striatum. Summarizing, the present studies exclude possibility that salsolinol under physiological conditions could be an endogenous factor involved in the neurogenerative processes; conversely, it can exert a protective action on nerve cells in the brain. These findings may have important implications for the development of the new strategies to treat or prevent neural degeneration.