In support of this hypothesis, following ingestion quercetin is present primarily as the aglycone or methylated metabolite in the brain, liver, lungs, and gut. Oral administration of quercetin reduces blood pressure in spontaneously hypertensive rats and stage hypertensive patients. In this way, glucuronidated avonoids may be concentrated in their more Aniracetam active aglycone form by cells responsible for inammatory damage.Flavonoid and metabolite concentrations in the brain A crucial issue in CNS drug discovery is whether sufcient amounts of a compound enter the brain.After oral administration, several avonoids have been detected in the rodent CNS, Carvacrol including epigallocatechin gallate and epicatechin metabolites, quercetin, and quercetin metabolites. Dietary supplementation with a grapederived polyphenolic preparation rich in catechin, epicatechin, catechin gallate, and epicatechin gallate attenuates cognitive decits and brain neuropathology in a transgenic mouse model of AD. Levels of these compounds in the brain were below the limit of detection; however, concentrations of their phase II metabolites were approximately pmolg tissue. To account for these ndings, it has been proposed that avonoids may increase resistance to oxidative stress by activating signaling pathways associated with cell survival. From the perspective of protecting neurons against oxidative stress, this is a particularly attractive hypothesis given evidence linking CREB activation to expression of peroxisome proliferatoractivated receptor gamma, a potent stimulator of mitochondrial biogenesis and respiration. There is now signicant support for the involvement of the CREB pathway in the neuroprotective and neurotrophic effects of different avonoid subtypes. These ndings clearly demonstrate that, at concentrations near those achieved physiologically, avonoids increase the phosphorylation of proteins that promote neuronal survival.Within this lower concentration range, a predominant class of enzymes inhibited by avonoids and their metabolites. Inhibition of PDE activity resulting in elevated cAMP signaling has recently been shown to mediate induction of mitochondrial biosynthesis and protection against oxidative stress by the polyphenolic resveratrol. This single mechanism therefore accounts for many of the ways in which avonoids may combat neurodegenerative disorders and provides a clear target with which to assist the clinical development of avonoidbased therapies. Moreover, this activity is preserved in the quercetin metabolite isorhamnetin, which reaches higher concentrations in blood than the aglycone. PDE is the most important isozyme of this large family for the function of neurons, airway smooth muscle, and almost all immune cells. Hesperetin potently reduces the expansion of macrophages, lymphocytes, neutrophils, and eosinophils and the release of proinammatory cytokines from these cells in a mouse model of asthma by blocking PDE. The induction of bglucuronidase in activated immune cells provides an important mechanism by which deconjugated avonoids may reach the concentrations necessary to inhibit PDE in these cells. Central PDE inhibition can be readily assessed in rodents by the reversal of ketaminexylazineinduced anesthesia.Compounds that inhibit this enzyme in the brain decrease the time spent by rodents in a recumbent position following administration of ketaminexylazine.Systemic administration of luteolin dosedependently reversed ketamine xylazine anesthesia, indicating that this avonoid achieves concentrations in brain sufcient to inhibit PDE. Brainpenetrant PDE inhibitors decrease neuroinammation and neurodegeneration in models of stroke, spinal cord injury, multiple sclerosis, AD, and PD.