X-Message-Number: 23370
Date: Tue, 3 Feb 2004 20:45:55 -0800 (PST)
From: Doug Skrecky <>
Subject: are flavonoids TRPM7 inhibitors?

Braz J Med Biol Res. 2003 Dec;36(12):1613-20. Epub 2003 Nov 17.
Neuroprotection by flavonoids.

	The high morbidity, high socioeconomic costs and lack of specific
treatments are key factors that define the relevance of brain pathology
for human health and the importance of research on neuronal protective
agents. Epidemiological studies have shown beneficial effects of flavonoids on
arteriosclerosis-related pathology in general and neurodegeneration in
particular. Flavonoids can protect the brain by their ability to modulate
intracellular signals promoting cellular survival. Quercetin and
structurally related flavonoids (myricetin, fisetin, luteolin) showed a marked
cytoprotective capacity in in vitro experimental conditions in models of
predominantly apoptotic death such as that induced by medium
concentrations (200 M) of H2O2 added to PC12 cells in culture.
Nevertheless, quercetin did not protect substantia nigra neurons in vivo
from an oxidative insult (6-hydroxydopamine), probably due to difficulties
in crossing the blood-brain barrier. On the other hand, treatment of
permanent focal ischemia with a lecithin/quercetin preparation decreased
lesion volume, showing that preparations that help to cross the
blood-brain barrier may be critical for the expression of the effects of
flavonoids on the brain. The hypothesis is advanced that a group of
quercetin-related flavonoids could become lead molecules for the
development of neuroprotective compounds with multitarget anti-ischemic

Kidney Int. 2003 Feb;63(2):554-63.
Bioflavonoids attenuate renal proximal tubular cell injury during cold
preservation in Euro-Collins and University of Wisconsin solutions.

	BACKGROUND: Cold ischemia and reperfusion during kidney
transplantation are associated with release of free oxygen radicals and
damage of renal tubular cells. Bioflavonoids may diminish cold
storage-induced injury due to antioxidant and iron chelating activities.
This study was designed to delineate the renoprotective mechanisms of
bioflavonoids and to define the structural features conferring
cytoprotection from cold injury. METHODS: LLC-PK1 cells were preincubated
for three hours with bioflavonoids and cold stored in University of
Wisconsin (UW)- or Euro-Collins (EC)-solution for 20
hours. After rewarming, cell viability was assessed by the lactate
dehydrogenase (LDH) release, MTT-test, and amino acid transport activity.
Lipid peroxidation was assessed from the generation of thiobarbituric
acid-reactive substances. RESULTS: Twenty-hours of cold storage of
LLC-PK1 cells resulted in a substantial loss of cell integrity that was
more pronounced in the EC (LDH release, 93.6 +/- 1.6%) than the UW
solution (67.2 +/- 6.9%; P < 0.0001). Pretreatment with quercetin
significantly enhanced cell survival (LDH release, 5.4 +/- 2.7% for UW
and 8.4 +/- 4.2% for EC) in a concentration dependent manner.
Structure-activity studies revealed similar renoprotection for
kaempferol, luteolin and fisetin, unlike myricetin, morin, apigenin,
naringenin, catechin, silibinin and rutin. Lipid peroxidation was reduced
(UW alone, 2.7 +/- 1.2 vs. UW+quercetin 0.5 +/- 0.2 nmol/mg protein, P <
0.01), and l-threonine uptake completely sustained by pretreatment with
quercetin, kaempferol, luteolin, and fisetin. However, renoprotection by
fisetin was rapidly lost during rewarming. Protective properties of
bioflavonoids were governed by the number and arrangement of hydroxyl
substitutes, electron-delocalization, sterical planarity, and
lipophilicity of the basic diphenylpyran skeleton. CONCLUSION: Cold
storage-induced renal tubular cell injury is ameliorated by
bioflavonoids. Renoprotective effects of bioflavonoids are defined by
structure, suggesting that flavonoids are incorporated into membrane lipid
bilayers and interfere with membrane lipid peroxidation.

Cell. 2003 Dec 26;115(7):863-877.
A Key Role for TRPM7 Channels in Anoxic Neuronal Death.

	Excitotoxicity in brain ischemia triggers neuronal death and
neurological disability, and yet these are not prevented by
antiexcitotoxic therapy (AET) in humans. Here, we show that in neurons
subjected to prolonged oxygen glucose deprivation (OGD), AET unmasks a
dominant death mechanism perpetuated by a Ca(2+)-permeable nonselective
cation conductance (I(OGD)). I(OGD) was activated by reactive
oxygen/nitrogen species (ROS), and permitted neuronal Ca(2+) overload and
further ROS production despite AET. I(OGD) currents corresponded to those
evoked in HEK-293 cells expressing the nonselective cation conductance
TRPM7. In cortical neurons, blocking I(OGD) or suppressing TRPM7
expression blocked TRPM7 currents, anoxic 45Ca(2+) uptake, ROS
production, and anoxic death. TRPM7 suppression eliminated the need for
AET to rescue anoxic neurons and permitted the survival of neurons
previously destined to die from prolonged anoxia. Thus, excitotoxicity is
a subset of a greater overall anoxic cell death mechanism, in which TRPM7
channels play a key role.

Rate This Message: http://www.cryonet.org/cgi-bin/rate.cgi?msg=23370