Diapocynin and apocynin administration fails to significantly extend survival in G93A SOD1 ALS mice
ABSTRACT NADPH oxidase has recently been identified as a promising new therapeutic target in ALS. Genetic deletion of NADPH oxidase (Nox2) in the transgenic SOD1(G93A) mutant mouse model of ALS was reported to increase survival remarkably by 97 days. Furthermore, apocynin, a widely used inhibitor of NADPH oxidase, was observed to dramatically extend the survival of the SOD1(G93A) ALS mice even longer to 113 days (Harraz et al. J Clin Invest 118: 474, 2008). Diapocynin, the covalent dimer of apocynin, has been reported to be a more potent inhibitor of NADPH oxidase. We compared the protection of diapocynin to apocynin in primary cultures of SOD1(G93A)-expressing motor neurons against nitric oxide-mediated death. Diapocynin, 10 μM, provided significantly greater protection compared to apocynin, 200 μM, at the lowest statistically significant concentrations. However, administration of diapocynin starting at 21 days of age in the SOD1(G93A)-ALS mouse model did not extend lifespan. Repeated parallel experiments with apocynin failed to yield protection greater than a 5-day life extension in multiple trials conducted at two separate institutions. The maximum protection observed was an 8-day extension in survival when diapocynin was administered at 100 days of age at disease onset. HPLC with selective ion monitoring by mass spectrometry revealed that both apocynin and diapocynin accumulated in the brain and spinal cord tissue to low micromolar concentrations. Diapocynin was also detected in the CNS of apocynin-treated mice. The failure to achieve significant protection with either apocynin or diapocynin raises questions about the utility for treating ALS patients.
- SourceAvailable from: Byunghee Henry Han[Show abstract] [Hide abstract]
ABSTRACT: Cerebral amyloid angiopathy (CAA) is characterized by deposition of amyloid β peptide (Aβ) within walls of cerebral arteries and is an important cause of intracerebral hemorrhage, ischemic stroke, and cognitive dysfunction in elderly patients with and without Alzheimer's Disease (AD). NADPH oxidase-derived oxidative stress plays a key role in soluble Aβ-induced vessel dysfunction, but the mechanisms by which insoluble Aβ in the form of CAA causes cerebrovascular (CV) dysfunction are not clear. Here, we demonstrate evidence that reactive oxygen species (ROS) and, in particular, NADPH oxidase-derived ROS are a key mediator of CAA-induced CV deficits. First, the NADPH oxidase inhibitor, apocynin, and the nonspecific ROS scavenger, tempol, are shown to reduce oxidative stress and improve CV reactivity in aged Tg2576 mice. Second, the observed improvement in CV function is attributed both to a reduction in CAA formation and a decrease in CAA-induced vasomotor impairment. Third, anti-ROS therapy attenuates CAA-related microhemorrhage. A potential mechanism by which ROS contribute to CAA pathogenesis is also identified because apocynin substantially reduces expression levels of ApoE-a factor known to promote CAA formation. In total, these data indicate that ROS are a key contributor to CAA formation, CAA-induced vessel dysfunction, and CAA-related microhemorrhage. Thus, ROS and, in particular, NADPH oxidase-derived ROS are a promising therapeutic target for patients with CAA and AD.Proceedings of the National Academy of Sciences 02/2015; 112(8). DOI:10.1073/pnas.1414930112 · 9.81 Impact Factor
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ABSTRACT: Accumulating evidence suggests that inflammatory mediators secreted by activated resident or infiltrated innate immune cells have a significant impact on the pathogenesis of neurodegenerative diseases. This may imply that patients affected by a neurodegenerative disease may benefit from treatment with selective inhibitors of innate immune activity. Here we review the therapeutic potential of apocynin, an essentially nontoxic phenolic compound isolated from the medicinal plant Jatropha multifida. Apocynin is a selective inhibitor of the phagocyte NADPH oxidase Nox2 that can be applied orally and is remarkably effective at low dose.BioMed Research International 07/2014; 2014:298020. DOI:10.1155/2014/298020 · 2.71 Impact Factor
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ABSTRACT: Rac1 is a major player of the Rho family of small GTPases that controls multiple cell signaling pathways, such as the organization of cytoskeleton (including adhesion and motility), cell proliferation, apoptosis and activation of immune cells. In the nervous system, in particular, Rac1 GTPase plays a key regulatory function of both actin and microtubule cytoskeletal dynamics and thus it is central to axonal growth and stability, as well as dendrite and spine structural plasticity. Rac1 is also a crucial regulator of NADPH-dependent membrane oxidase (NOX), a prominent source of reactive oxygen species (ROS), thus having a central role in the inflammatory response and neurotoxicity mediated by microglia cells in the nervous system. As such, alterations in Rac1 activity might well be involved in the processes that give rise to Amyotrophic Lateral Sclerosis (ALS), a complex syndrome where cytoskeletal disturbances in motor neurons and redox alterations in the inflammatory compartment play pivotal and synergic roles in the final disease outcomes. Here we will discuss the genetic and mechanistic evidence indicating the relevance of Rac1 dysregulation in the pathogenesis of ALS.Frontiers in Cellular Neuroscience 09/2014; 8:279. DOI:10.3389/fncel.2014.00279 · 4.18 Impact Factor