Neuroprotection of Lubeluzole Is Mediated Through the Signal Transduction Pathways of Nitric Oxide

Abstract

Neuronal survival after ischemic injury is determined through the induction of several biological pathways. We examined whether lubeluzole, an agent efficacious in both clinical and experimental models of cerebral ischemia, modulated the signal transduction mechanisms of nitric oxide (NO), a downstream mediator of anoxic neurodegeneration. Both pretreatment [NO survival = 23 ± 3%, NO/lubeluzole (750 nM) survival = 63 ± 2%, p < 0.001] and coadministration [NO survival = 25 ± 3%, NO/lubeluzole (750 nM) survival = 59 ± 3%, p < 0.001] of lubeluzole with NO generators equally protected cultured hippocampal neurons in a dose‐dependent manner against the toxic effects of NO, suggesting that the agent protects by acutely modifying toxic cellular pathways rather than preconditioning the neuron before injury. The protection observed with lubeluzole was stereospecific but was not limited to pre‐ or coadministration. Lubeluzole also was found to significantly protect against the toxicity of NO for a period of 4–6 h after NO exposure [NO survival = 31 ± 2%, NO/lubeluzole (750 nM) survival at 6 h = 56 ± 3%, p < 0.001]. We conclude that the neuroprotective ability of lubeluzole is unique and involves the direct modulation of the NO pathway. In addition, the mechanisms of NO toxicity are dynamic and reversible processes that, if left unaltered, will lead to neuronal injury. Further investigation of the downstream signal transduction mechanisms below the level of NO generation may elucidate the specific cellular events responsible for neurodegeneration.

Erythropoietin: Elucidating new cellular targets that broaden therapeutic strategies

“…As an example, externalization of membrane PS residues occurs in neurons during anoxia (Maiese, 2001;Maiese and Boccone, 1995;, nitric oxide exposure (Chong et al, 2003f;Maiese et al, 1997), and during the administration of agents that induce the production of reactive oxygen species, such as 6-hydroxydopamine (Salinas et al, 2003). Membrane PS externalization on platelets also has been associated with clot formation in the vascular cell system (Leytin et al, 2006).…”

Contribution of Downregulation of L-type Calcium Currents to Delayed Neuronal Death in Rat Hippocampus after Global Cerebral Ischemia and Reperfusion

“…Accordingly, we next mimicked the in vivo ischemia-induced pyramidal neuron death by using NO-related SNP-induced toxicity (Maiese et al, 1997) in cultured hippocampal neurons and test the effects of SNP and Bay K8644 on the currents.…”

Neuroprotective effect of naphtha[1,2-d]thiazol-2-amine in an animal model of Parkinson's disease

“…Lubeluzole (Figure 1), a novel benzothiazole compound which currently has tested antiischemic in clinical and preclinical studies has been shown to attenuate growth of ischemic damage as well as its density in the periphery of a photochemically induced neocortical infarct in rats [19]. It is a NOS inhibitor, which in addition decreases glutamate release and blocks sodium and calcium channels [20,21]. Another example of an analogue with an aminothiazole moiety is riluzole (Figure 1), a novel neuroprotective drug that is approved worldwide for the treatment of amyotrophic lateral sclerosis and is active in a wide variety of experimental models of neurodegenerative diseases, including toxin-induced models of PD in rodent and primate [22][23][24][25].…”