Ischemic stroke is a heterogenous and dynamic process that remains a major healthcare problem. It triggers multiple cytotoxic pathways that evolve through time, including excitotoxicity, oxidative/nitrosative stress, inflammation, blood-brain barrier (BBB) degradation, and apoptosis. Without immedia...
Ischemic stroke is a heterogenous and dynamic process that remains a major healthcare problem. It triggers multiple cytotoxic pathways that evolve through time, including excitotoxicity, oxidative/nitrosative stress, inflammation, blood-brain barrier (BBB) degradation, and apoptosis. Without immediate reperfusion, salvageable penumbra area can transform into irreversibly damaged tissue. Thrombolysis with tissue plasminogen activator (tPA) is the only Food and Drug Administration (FDA)-approved therapy for ischemic stroke. Despite the successful recanalization by tPA, its therapeutic application remains limited, highly imposed by narrow therapeutic time window due to reperfusion injury and the risk of intracerebral hemorrhage (ICH) and mortality. Delayed tPA treatment exerts various detrimental effects, such as excitotoxicity, radical formation, inflammation, and BBB degradation, which occur commonly in ischemia-evoked brain damage as well. Hence, intervention of multitarget-directed neuroprotectant (MTDN) would be a strategic approach to concurrently combat the multiple cytotoxic pathways of ischemic stroke and tPA. Previously, SP-8203 has been reported to block the N-methyl-D-aspartate (NMDA)-induced excitotoxicity in cultured mouse cortical neurons mixed with glial cells and elevate SOD activity in SH-SY5Y cells in vitro. Moreover, in separate in vitro studies conducted by my colleagues, they found out that SP-8203 increased the expression of manganese superoxide dismutase (Mn-SOD) and inhibited the release of pro-inflammatory cytokines/chemokine and the migration of inflammatory cells. Hence, I postulated that SP-8203 can be developed as a promising MTDN for ischemic stroke therapy, as a single treatment as well as a combined treatment with tPA. Taken together, this translational stroke research-based thesis consists of 3 comprehensive preclinical studies aiming to assess the therapeutic efficacy and safety of SP-8203 alone and in combination with tPA (as demonstrated in Study 1 and Study 2, respectively), and also to discover the potential of SP-8203 to extend the thrombolytic time window of tPA (as demonstrated in Study 3).
In Study 1, I demonstrated that SP-8203 alone can effectively provide brain protection against ischemic/reperfusion (I/R) injury in transient focal cerebral ischemia rats (1.5 h MCAO) up to 6 h post-ischemia via multiple mechanisms such as suppressing the release of inflammatory mediators and the recruitment of inflammatory cells, as well as inhibiting the formation of inducible nitric oxide synthase (iNOS) and the resulting nitrotyrosine. I also disclosed that SP-8203 is a safe, well-tolerated and metabolically stable drug, in animals and humans. Next in Study 2, to investigate the safety and efficacy of SP-8203 in combination with tPA, first, I successfully established a reproducible clot-based embolic stroke model in rats. By using my rat embolic stroke model, the early thrombolysis achieved by tPA (within 3-4.5h of embolism) improved therapeutic efficacy with higher risk of death and greater chance to develop ICH after embolism. While delayed tPA treatment beyond 4.5 h after embolism not only failed to provide therapeutic efficacy, it also greatly increased the incidence of mortality and ICH. Interestingly, co-administration of SP-8203 and tPA at 4.5 h after embolism prevented the tPA-evoked mortality and ICH in embolic stroke rats, although no improved therapeutic efficacy was observed. Furthermore, the rat ex vivo platelet aggregation assays showed that SP-8203 did not have anti-platelet activities, have further ensured the safety profile of combining SP-8203 with tPA. After confirming the safety and efficacy of SP-8203 alone and in combination with tPA, I advanced my investigation on whether SP-8203 can extend the therapeutic time window of tPA to 6 h after embolism, in Study 3. Here, I demonstrated that pre-treatment (1.5 h before tPA) of SP-8203 markedly decreased the delayed tPA (6 h after embolism)-evoked mortality and ICH in embolic stroke rats, even though no improved therapeutic efficacies were observed. I also demonstrated that impediment of tPA-evoked ICH by SP-8203 following ischemia could be related with suppression of MMP-2/9 activity which leads to the protection of the vascular unit.
In summary, SP-8203 is a pleiotropic anti-ischemia agent which suppresses the generation of reactive oxygen/nitrogen species, inhibits the recruitment and activation of inflammatory cells, and prevents the upregulation of MMP-2/9 following cerebral ischemia. Combined treatment of SP-8203 with tPA in ischemic stroke may improve the clinical use of tPA by reducing tPA-evoked adverse effects, consequently extending the therapeutic time window of tPA. Thanks to its multiple neuroprotective mechanisms, SP-8203 could be developed as a promising drug candidate for stroke treatment, alone and in combination with tPA. Furthermore, my thesis demonstrates the superiority of MTDN use for ischemic stroke therapy and further supports the novel therapeutic approach of combining tPA with MTDN to improve clinical stroke outcomes.
Ischemic stroke is a heterogenous and dynamic process that remains a major healthcare problem. It triggers multiple cytotoxic pathways that evolve through time, including excitotoxicity, oxidative/nitrosative stress, inflammation, blood-brain barrier (BBB) degradation, and apoptosis. Without immediate reperfusion, salvageable penumbra area can transform into irreversibly damaged tissue. Thrombolysis with tissue plasminogen activator (tPA) is the only Food and Drug Administration (FDA)-approved therapy for ischemic stroke. Despite the successful recanalization by tPA, its therapeutic application remains limited, highly imposed by narrow therapeutic time window due to reperfusion injury and the risk of intracerebral hemorrhage (ICH) and mortality. Delayed tPA treatment exerts various detrimental effects, such as excitotoxicity, radical formation, inflammation, and BBB degradation, which occur commonly in ischemia-evoked brain damage as well. Hence, intervention of multitarget-directed neuroprotectant (MTDN) would be a strategic approach to concurrently combat the multiple cytotoxic pathways of ischemic stroke and tPA. Previously, SP-8203 has been reported to block the N-methyl-D-aspartate (NMDA)-induced excitotoxicity in cultured mouse cortical neurons mixed with glial cells and elevate SOD activity in SH-SY5Y cells in vitro. Moreover, in separate in vitro studies conducted by my colleagues, they found out that SP-8203 increased the expression of manganese superoxide dismutase (Mn-SOD) and inhibited the release of pro-inflammatory cytokines/chemokine and the migration of inflammatory cells. Hence, I postulated that SP-8203 can be developed as a promising MTDN for ischemic stroke therapy, as a single treatment as well as a combined treatment with tPA. Taken together, this translational stroke research-based thesis consists of 3 comprehensive preclinical studies aiming to assess the therapeutic efficacy and safety of SP-8203 alone and in combination with tPA (as demonstrated in Study 1 and Study 2, respectively), and also to discover the potential of SP-8203 to extend the thrombolytic time window of tPA (as demonstrated in Study 3).
In Study 1, I demonstrated that SP-8203 alone can effectively provide brain protection against ischemic/reperfusion (I/R) injury in transient focal cerebral ischemia rats (1.5 h MCAO) up to 6 h post-ischemia via multiple mechanisms such as suppressing the release of inflammatory mediators and the recruitment of inflammatory cells, as well as inhibiting the formation of inducible nitric oxide synthase (iNOS) and the resulting nitrotyrosine. I also disclosed that SP-8203 is a safe, well-tolerated and metabolically stable drug, in animals and humans. Next in Study 2, to investigate the safety and efficacy of SP-8203 in combination with tPA, first, I successfully established a reproducible clot-based embolic stroke model in rats. By using my rat embolic stroke model, the early thrombolysis achieved by tPA (within 3-4.5h of embolism) improved therapeutic efficacy with higher risk of death and greater chance to develop ICH after embolism. While delayed tPA treatment beyond 4.5 h after embolism not only failed to provide therapeutic efficacy, it also greatly increased the incidence of mortality and ICH. Interestingly, co-administration of SP-8203 and tPA at 4.5 h after embolism prevented the tPA-evoked mortality and ICH in embolic stroke rats, although no improved therapeutic efficacy was observed. Furthermore, the rat ex vivo platelet aggregation assays showed that SP-8203 did not have anti-platelet activities, have further ensured the safety profile of combining SP-8203 with tPA. After confirming the safety and efficacy of SP-8203 alone and in combination with tPA, I advanced my investigation on whether SP-8203 can extend the therapeutic time window of tPA to 6 h after embolism, in Study 3. Here, I demonstrated that pre-treatment (1.5 h before tPA) of SP-8203 markedly decreased the delayed tPA (6 h after embolism)-evoked mortality and ICH in embolic stroke rats, even though no improved therapeutic efficacies were observed. I also demonstrated that impediment of tPA-evoked ICH by SP-8203 following ischemia could be related with suppression of MMP-2/9 activity which leads to the protection of the vascular unit.
In summary, SP-8203 is a pleiotropic anti-ischemia agent which suppresses the generation of reactive oxygen/nitrogen species, inhibits the recruitment and activation of inflammatory cells, and prevents the upregulation of MMP-2/9 following cerebral ischemia. Combined treatment of SP-8203 with tPA in ischemic stroke may improve the clinical use of tPA by reducing tPA-evoked adverse effects, consequently extending the therapeutic time window of tPA. Thanks to its multiple neuroprotective mechanisms, SP-8203 could be developed as a promising drug candidate for stroke treatment, alone and in combination with tPA. Furthermore, my thesis demonstrates the superiority of MTDN use for ischemic stroke therapy and further supports the novel therapeutic approach of combining tPA with MTDN to improve clinical stroke outcomes.
주제어
#SP-8203 ischemic stroke multitarget-directed tissue plasminogen activator intracerebral hemorrhage
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