Is salsolinol a friend or foe? Revisiting its roles in neurotoxicity and cellular protection

Salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, SAL) is a dopamine-derived tetrahydroisoquinoline, first identified in the urine of a Parkinson's disease patient treated with L-DOPA. SAL is generated endogenously via both enzymatic and non-enzymatic Pictet-Spengler condensation of dopamine with acetaldehyde. It is also found in dietary sources such as bananas, mushrooms, and cocoa, as well as in certain microbes. SAL has been detected in cerebrospinal fluid and various brain regions. SAL acts as a neuroactive compound implicated in ethanol's reinforcing effects and has been proposed as an endogenous prolactin-releasing factor. Its structural similarity to the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) has long provoked suspicions that SAL may induce dopaminergic neurodegeneration through generation of reactive oxygen species and subsequent activation of cell death pathways. However, recent in vitro and in vivo studies reveal a biphasic profile: at low concentrations, SAL exerts neuroprotective effects, whereas at higher concentrations, it becomes neurotoxic. This review therefore summarizes differential pathophysiological roles of SAL based on experimental and clinical findings, highlighting its context-specific, dose-dependent actions in the central nervous system.