Neuroprotective and antioxidant properties of new quinolylnitrones in in vitro and in vivo cerebral ischemia models

Cerebral ischemia is a condition affecting an increasing number of people worldwide, and the main cause of disability. Current research focuses on the search for neuroprotective drugs for its treatment, based on the molecular targets involved in the ischemic cascade. Nitrones are potent antioxidant molecules that can reduce oxidative stress. Here we report the neuroprotective properties and the antioxidant power of the six new quinolylnitrones (QNs) 1-6 for their potential application in stroke therapy. QNs 1-4 are 2-chloro-8-hydroxy-substituted QNs bearing N-t-butyl or N-benzyl substituents at the nitrone motif located at C3, whereas QN5 and QN6 are 8-hydroxy QNs bearing N-t-butyl or N-benzyl substituents at the nitrone motif located at C2, respectively. In vitro neuroprotection studies using QNs 1-6 in an oxygen-glucose-deprivation model of cerebral ischemia, in human neuroblastoma cell cultures, indicate that all QNs have promising neuroprotective, anti-necrotic, anti-apoptotic, and anti-oxidant properties against experimental ischemia-reperfusion in neuronal cultures. QN6 stands out as the most balanced nitrone out of all tested QNs, as it strongly prevents decreased neuronal metabolic activity (EC50 = 3.97 +/- 0.78 mu M), as well as necrotic (EC50 = 3.79 +/- 0.83 mu M) and apoptotic cell death (EC50 = 3.99 +/- 0.21 mu M). QN6 showed high capacity to decrease superoxide production (EC50 = 3.94 +/- 0.76 mu M), similar to its parent molecule alpha-phenyl-tert-butyl nitrone (PBN) and the well-known anti-oxidant molecule N-acetyl-l-cysteine (NAC). Thus, QN6 demonstrated the highest antioxidant power out of the other tested QNs. Finally, in vivo treatment with QN6 in an experimental permanent stroke model elicited a significant reduction (75.21 +/- 5.31%) of the volume size of brain lesion. Overall, QN6 is a potential agent for the therapy of cerebral ischemia that should be further investigated.

Automated summary

Cerebral ischemia is a growing global problem and the leading cause of disability. Researchers have focused on finding neuroprotective drugs that target the molecular processes involved in cerebral ischemia. Six new quinolylnitrones (QNs) have been discovered, which show promising neuroprotective and antioxidant properties against ischemia-reperfusion in neuronal cultures. Among these QNs, QN6 demonstrates the highest antioxidant power and neuroprotective effect, making it a potential candidate for cerebral ischemia therapy.