ZL006 promotes migration and differentiation of transplanted neural stem cells in male rats after stroke

    loading  Checking for direct PDF access through Ovid


Ischemic stroke is induced by decreased blood supply to the brain followed by neurological function impairments (Flynn, MacWalter, & Doney, 2008), which is a leading cause of disability and death worldwide (Sims & Muyderman, 2010). The biological processes of stroke are extremely complicated. Neurons, glia, and vascular elements are all involved in mechanisms of tissue injury and repair, and many biomolecules participate in the initiation, progression, and recovery of this fatal disease (Moskowitz, Lo, & Iadecola, 2010). Since 1995, tissue plasminogen activator has been the most popular clinical drug for victims of stroke (Hacke et al., 1995). As a thrombolytic drug, it works only in the early stage of ischemia and increases the risk of cerebral hemorrhage (Ning et al., 2010). In addition, only about 5% of stroke patients receive this treatment throughout the United States (Cramer et al., 2012).
Although great efforts have been made, the therapy for stroke is still limited (Henninger, Kumar, & Fisher, 2010). In recent years, stem cell–based therapy, as the prospective treatment for stroke, has been given more attention (Kokaia & Darsalia, 2011). Transplanted neural stem cells (NSCs) improved both functional and structural outcome after stroke (Chen, Zhang, Gu, & Guo, 2016). There are a lot of factors involved in NSC transplantation. For example, brain‐derived neurotrophic factor (BDNF) is critical for survival of transplanted NSCs. Human NSCs overexpressing BDNF showed an improved survival rate when transplanted into intracerebral hemorrhage rats and could provide increase angiogenesis and functional recovery in a mouse intracerebral hemorrhage model (Lee, Lim, Lee, & Kim, 2010). Additionally, electrical stimulation might be a selective nondrug approach for activating endogenous and transplanted NSCs in the central nervous system (Huang, Li, Chen, Zhou, & Tan, 2015).
ZL006 is 5‐(3,5‐dichloro‐2‐hydroxybenzylamino)‐2‐hydroxybenzoic acid, which was designed and synthesized in our previous study (Zhou et al., 2010). This compound can disrupt the interaction of neuronal nitric oxide synthase (nNOS) with postsynaptic density protein‐95 (PSD‐95) effectively and specifically (Zhou et al., 2010). nNOS is mainly expressed in neurons (Thomas & Feron, 1997), though much wider distribution in other cell types in the brain has been demonstrated (Zhou & Zhu, 2009). It binds to N‐methyl‐D‐aspartate receptor (NMDAR) through a scaffolding protein PSD‐95 at the excitatory synapses, forming a macromolecular signaling complex (Aarts et al., 2002). Activation of nNOS depends on NMDAR‐mediated calcium influx and on its association with PSD‐95 (Sattler et al., 1999). Cerebral ischemia induces increased interaction of nNOS with PSD‐95, leading to nitric oxide overproduction and neuronal injury (Zhou et al., 2010). So, the small molecular inhibitor of nNOS–PSD‐95 interaction substantially reduces ischemic damage (Zhou et al., 2010). Moreover, we have found that nNOS in NSCs is positive, whereas nNOS in neurons is negative to neurogenesis (Luo et al., 2010). Increased nNOS–PSD‐95 interaction in neurons after ischemia will certainly inhibit neurogenesis, which was subsequently demonstrated by us (Luo et al., 2014). Meanwhile, we reported that uncoupling nNOS–PSD‐95 in neurons with ZL006 promotes neuronal differentiation of endogenous NSCs, facilitates survival and migration of these newborn cells, and enhances their neurite growth in the ischemic brain of male rats (Luo et al., 2014). However, it is unknown whether uncoupling nNOS–PSD‐95 in host neurons will benefit the fate of transplanted NSCs after stroke.
Therefore, we hypothesized that uncoupling nNOS–PSD‐95 would promote survival, migration, and differentiation of transplanted NSCs after stroke and, consequently, improve the functional outcome. In this study, we focused on the effect of ZL006 in male rats after focal cerebral ischemia.

Related Topics

    loading  Loading Related Articles