Priming of cultured neurons with sabeluzole results in long-lasting inhibition of neurotoxin-induced tau expression and cell death

Abstract

Sabeluzole was described to have antiischemic, antiepileptic, and cognitive-enhancing properties, and is currently under development for Alzheimer's disease. Recently, it was reported that repeated treatments with sabeluzole protect cultured rat hippocampal neurons against NMDA-and glutamate-induced neurotoxicity. We evaluated the possibility that sabeluzole elicits neuroprotection by acting, either directly or indirectly, on tau proteins. We found that repeated treatments during development of primary cultures of cerebellar granule cells with nanomolar concentrations of sabeluzole resulted in mature cells that were resistant to the excitotoxicity induced by glutamate. Also, sabeluzole treatment specifically prevented the glutamateinduced increase of tau expression without modifying the basal pattern of expression of tau proteins, as shown by measurement of mRNA and protein levels. In human neuroblastoma cell line SH-SY5Y, differentiated by treatment with retinoic acid, doxorubicin increased tau immunoreactivity, and later induced cell death. Both effects were prevented by sabeluzole. Our data indicate that increased tau expression is a common response to different types of cells to neurotoxic agents, and that sabeluzoleinduced neuroprotection is functionally associated with the prevention of the injurymediated increase of tau expression.

Quinolinic acid induces neuritogenesis inSH‐SY5Y neuroblastoma cells independently ofNMDAreceptor activation

“…The expression of NMDA receptors in SH‐SY5Y neuroblastoma cells has long been controversial (Tetich et al ., ; Park et al ., ) although they have been used as negative controls for the presence of functional glutamate receptors (Uberti et al ., ; Glantz et al ., ). RA‐induced differentiation has been reported to induce the appearance of NR1 subunits in SH‐SY5Y cells (Kulikov et al ., ), but that was not observed in the present study in which the absence of any response to NMDA was consistent with patch‐clamp studies which failed to detect any ionotropic responses to NMDA (Jantas et al ., ).…”

The glutamatergic system and neurodegeneration in dementia: preventive strategies in Alzheimer's disease

“…Glutamate and aspartate can also induce PHF formation in cultured human neurons similar to those seen in AD brains (De Boni and McLachlan, 1985). Glutamate-induced increase of tau expression might be prevented with sabeluzoletype drugs (Uberti et al, 1997) and other compounds (MU-801, HP-7) (Couratier et al, 1996).…”

Phospho-Tau Protein Expression in the Cell Cycle of SH-SY5Y Neuroblastoma Cells: A Morphological Study

“…In contrast, these markers do not colocalize in the cytoplasm (merged image, arrowhead). [16,47,48]. It has been suggested that the role of tau nucleus [16,45].…”

“…Previous studies in neuroblastoma cells described the presence of non-phosphorylated tau protein recognized by the Tau-1 antibody in the nucleolus. During cell cycle, Tau-1 immunoreactivity exhibits granular staining associated with chromosomes, suggesting that tau protein might have some normal physiological functions not necessarily associated with microtubules [16,47,48]. It has been suggested that the role of tau depends on the functional status and development of the cell, which hints that tau protein may exert different functions.…”