Mitochondrial targeting of XJB-5-131 attenuates or improves pathophysiology in HdhQ150 animals with well-developed disease phenotypes

Abstract

Oxidative damage to mitochondria (MT) is a major mechanism for aging and neurodegeneration. We have developed a novel synthetic antioxidant, XJB-5-131, which directly targets MT, the primary site and primary target of oxidative damage. XJB-5-131 prevents the onset of motor decline in an HdhQ(150/150) mouse model for Huntington's disease (HD) if treatment starts early. Here, we report that XJB-5-131 attenuates or reverses disease progression if treatment occurs after disease onset. In animals with well-developed pathology, XJB-5-131 promotes weight gain, prevents neuronal death, reduces oxidative damage in neurons, suppresses the decline of motor performance or improves it, and reduces a graying phenotype in treated HdhQ(150/150) animals relative to matched littermate controls. XJB-5-131 holds promise as a clinical candidate for the treatment of HD.

The chicken or the egg: mitochondrial dysfunction as a cause or consequence of toxicity in Huntington’s disease

“…Oxidative lesion levels has been measured directly in DNA of mouse brains from HdhQ(150/150) mouse models (Budworth et al, 2015; Polyzos et al, 2016) and in STHdhQ 111 cells (Siddiqui et al, 2012). Quantitative PCR (Polyzos et al, 2016) and 8-oxo-G antibodies (Polyzos et al, 2016) confirm a rise in oxidative DNA damage in both mtDNA and in nuclear DNA. But is this increase of oxidative DNA lesions relevant to disease?…”

“…But is this increase of oxidative DNA lesions relevant to disease? In the FL HdhQ(150/150) mouse model, there is no observable oxidative damage in MT at 12–16wks, but damage becomes obvious at 60–80wks, well after motor deficits are observed (Budworth et al, 2016;Polyzos et al, 2016). These data suggest that oxidation in the mitochondrial genome occurs, but is late in disease progression, and is not the primary source cause of toxicity.…”

“…XJB-5-131 is a synthetic radical scavenger that targets an antioxidant to the inner mitochondrial membrane (Polyzos et al, 2016 and refs within). In the HdhQ(150/150) animals, XJB-5-131 targeting attenuates the decline in Rota-Rod performance, suppresses weight loss, and attenuates mitochondrial lesion load and mitochondrial copy number if treatment begins at a young age before phenotypes develop (Xun et al, 2012), attenuates or reverses the effects of disease if treatment begins after disease onset (Polyzos et al, 2016).…”

“…XJB-5-131 is a synthetic radical scavenger that targets an antioxidant to the inner mitochondrial membrane (Polyzos et al, 2016 and refs within). In the HdhQ(150/150) animals, XJB-5-131 targeting attenuates the decline in Rota-Rod performance, suppresses weight loss, and attenuates mitochondrial lesion load and mitochondrial copy number if treatment begins at a young age before phenotypes develop (Xun et al, 2012), attenuates or reverses the effects of disease if treatment begins after disease onset (Polyzos et al, 2016). In aging animals with well-developed pathology, XJB-5-131 treatment promotes weight gain, attenuates neuronal loss, reduces inclusion formation, prevents the performance decline in multiple motor tests, suppresses somatic expansion, and decreases oxidative damage in the brains of aging HdhQ(150/150) animals relative to age-matched vehicle-treated HdhQ(150/150) or HdhQ(wt/wt) animals.…”

“…Most important in addressing the relationship to oxidative damage, treatment with XJB-5-131, attenuates mitochondrial lesion load, mitochondrial copy number, and somatic expansion (Budworth et al, 2016). The staining with 8-oxo-G antibodies is prominent in MT and colocalize with the Voltage-dependent anion channel (VDAC), which is a mitochondrial marker (Polyzos et al, 2016), and is also reversed by XJB-5-131. In sum, treatment with this electron scavenger reduces oxidative damage in MT and suppresses both somatic expansion and disease phenotypes.…”