The flavonoid-enriched fraction AF4 suppresses neuroinflammation and promotes restorative gene expression in a mouse model of experimental autoimmune encephalomyelitis.

The anti-inflammatory and restorative effects of the flavonoid-enriched fraction AF4 were examined in a mouse model of experimental autoimmune encephalomyelitis (EAE). Relative to EAE mice that received vehicle (water, 10 ml/kg/day), oral administration of AF4 (25mg/kg/day) beginning 24h after the onset of clinical signs reduced disease severity from days 19-31 post-immunization. AF4-mediated recovery from EAE was preceded by reduced plasma concentrations of TNFα and IL-1ß on day 18 followed by decreased cytokine production and neuropathology in the cerebellum and spinal cord on day 31. Clinical improvement for EAE-AF4 mice from days 18 to 31 was accompanied by the elevated expression of genes that mediate remyelination. These findings suggest that AF4 decreased EAE severity by promoting the resolution of inflammation and improving functional recovery in the CNS.

Neuroprotective and anti-inflammatory effects of the flavonoid-enriched fraction AF4 in a mouse model of hypoxic-ischemic brain injury.

We report here neuroprotective and anti-inflammatory effects of a flavonoid-enriched fraction isolated from the peel of Northern Spy apples (AF4) in a mouse of model of hypoxic-ischemic (HI) brain damage. Oral administration of AF4 (50 mg/kg, once daily for 3 days) prior to 50 min of HI completely prevented motor performance deficits assessed 14 days later that were associated with marked reductions in neuronal cell loss in the dorsal hippocampus and striatum. Pre-treatment with AF4 (5, 10, 25 or 50 mg/kg, p.o.; once daily for 3 days) produced a dose-dependent reduction in HI-induced hippocampal and striatal neuron cell loss, with 25 mg/kg being the lowest dose that achieved maximal neuroprotection. Comparison of the effects of 1, 3 or 7 doses of AF4 (25 mg/kg; p.o.) prior to HI revealed that at least 3 doses of AF4 were required before HI to reduce neuronal cell loss in both the dorsal hippocampus and striatum. Quantitative RT-PCR measurements revealed that the neuroprotective effects of AF4 (25 mg/kg; p.o.; once daily for 3 days) in the dorsal hippocampus were associated with a suppression of HI-induced increases in the expression of IL-1ß, TNF-α and IL-6. AF4 pre-treatment enhanced mRNA levels for pro-survival proteins such as X-linked inhibitor of apoptosis and erythropoietin following HI in the dorsal hippocampus and striatum, respectively. Primary cultures of mouse cortical neurons incubated with AF4 (1 µg/ml), but not the same concentrations of either quercetin or quercetin-3-O-glucose or its metabolites, were resistant to cell death induced by oxygen glucose deprivation. These findings suggest that the inhibition of HI-induced brain injury produced by AF4 likely involves a transcriptional mechanism resulting from the co-operative actions of various phenolics in this fraction which not only reduce the expression of pro-inflammatory mediators but also enhance pro-survival gene signalling.

Target-based selection of flavonoids for neurodegenerative disorders.

Habitual consumption of dietary flavonoids known to improve mitochondrial bioenergetics and inhibit various secondary sources of reactive oxygen species (ROS) reduces the risk for neurodegenerative disorders such as Parkinson's disease (PD), stroke, and Alzheimer's disease (AD). Combining specific dietary flavonoids selected on the basis of oral bioavailability, brain penetration, and the inhibition of multiple processes responsible for excessive ROS production may be a viable approach for the prevention and treatment of neurodegenerative disorders. Inclusion of flavonoids that raise cAMP levels in the brain may be of additional benefit by reducing the production of proinflammatory mediators and stimulating the transcriptional machinery necessary for mitochondrial biosynthesis. Preclinical models suggest that flavonoids reduce hearing loss resulting from treatment with the chemotherapeutic drug cisplatin by opposing the excessive production of ROS and proinflammatory mediators implicated in PD, stroke, and AD. Flavonoid combinations optimized for efficacy in models of cisplatin-induced hearing loss (CIHL) may therefore have therapeutic utility for neurodegenerative disorders.

Heat shock proteins protect against ischemia and inflammation through multiple mechanisms.

After heat shock or other metabolic stress, heat shock proteins (Hsps) are expressed at high levels in all tissues and cells. The highly inducible 70 kDa heat shock protein (Hsp70) is associated with improved post-ischemic myocardial contractile recovery. Similarly, the small 27 kDa heat shock protein (Hsp27), that is abundant in muscle, is also linked with improved myocardial function after ischemic injury. Various Hsps have pro-survival functions that include chaperone, anti-apoptotic and/or anti-inflammatory activity. In this review we will summarize our understanding of myocardial protection and present evidence for protection having time dependent aspects that appear to be stimulus dependent.