Responses at both early and middle stages of the disease with modest (4 week) treatment. While encouraging overall, additional concerns and questions still need to be addressed prior to further considerations in a clinical population. While RyR2 is extensively expressed in AD-vulnerable brain regions, it is also highly expressed in cardiac muscle. While in the present study sub-chronic dantrolene treatment did not have any detectable adverse side effects on development,body weight or cardiac weight, these are features that must be watched closely in candidate patients for long-term dantrolene treatment. Further, dantrolene has differential inhibitory properties on Ca2+ release for the three RyR isoforms, with the relatively weakest effects on RyR2 [48]. Thus, a compound more specific for stabilizing RyR2 and targeted to the brain could be optimal for AD therapeutics. It is also important to consider the role of the RyR3, as it is upregulated at disease stages coincident with Ab1?2 deposition, and is thought to be a potential neuroprotective response to amyloid exposure [49]. To advance AD drug discovery, there needs to be a shift in current research priorities to address newer concepts. This includes strategies that target the Ca2+ signaling disruptions which are imbedded in all the major features and risk factors for AD. Compounds that would normalize aberrant Ca2+ signaling could likely impede pathogenic cascades, and alter the course of the disease rather than merely delay the progression of cognitive symptoms. Financial Disclosure: JCR is employed by R D China, U.K Group, GlaxoSmithKline; BC and VGC are employed by Lyotropic Therapeutics.Figure 6. Dantrolene treatment reduces amyloid load in AD mice. (A) Representative 4G8-immunostained tissue from saline-treated (left) and dantrolene-treated (right) 6-month old TASTPM mice demonstrate an approximate 45 reduction in amyloid density with dantrolene treatment. (B) Averaged bar graphs show significant reduction in amyloid peptide staining in both the hippocampus (left) and cortex (right) in the dantrolenetreated mice compared to saline-treated mice. (C) Representative thioflavin S stained tissue from saline-treated (left) and dantrolene-treated (right) 6month old TASTPM mice show an approximate 42 reduction in amyloid density with drug treatment. (D) Averaged bar graphs show significant reduction in the density of dense core amyloid plaques in both the hippocampus (left) and cortex (right) in the dantrolene-treated mice (white bars) compared to saline-treated mice (black bars). * = p,0.05, scale bar = 250 mm, n = 4? mice per group. doi:10.1371/journal.pone.0052056.CX-4945 gNormalizing ER Ca2+ for AD TreatmentAuthor ContributionsConceived and designed the experiments: GES SC CB. Performed the experiments: SC CB MBM IG CS JK JW. Analyzed the data: SC CBMBM IG CS JK JW GES. Contributed reagents/materials/analysis tools: JCR VC BGC. Wrote the paper: GES SC CB.
Cardiovascular diseases, the leading cause of morbidity and mortality in industrialized countries are predominantly caused by atherosclerosis. This is an inflammatory disease, the result of a cascade of events in blood vessels, leading to remodelling of the arterial wall, and a subsequent reduction in lumen size. In recent years, traditional risk factors for atherosclerosis 18325633 (such as hypertension and hypercholesterolemia) have also been associated with decreased numbers and impaired function of circulating MedChemExpress CP-868596 endothelial progenitor cells (EPCs.Responses at both early and middle stages of the disease with modest (4 week) treatment. While encouraging overall, additional concerns and questions still need to be addressed prior to further considerations in a clinical population. While RyR2 is extensively expressed in AD-vulnerable brain regions, it is also highly expressed in cardiac muscle. While in the present study sub-chronic dantrolene treatment did not have any detectable adverse side effects on development,body weight or cardiac weight, these are features that must be watched closely in candidate patients for long-term dantrolene treatment. Further, dantrolene has differential inhibitory properties on Ca2+ release for the three RyR isoforms, with the relatively weakest effects on RyR2 [48]. Thus, a compound more specific for stabilizing RyR2 and targeted to the brain could be optimal for AD therapeutics. It is also important to consider the role of the RyR3, as it is upregulated at disease stages coincident with Ab1?2 deposition, and is thought to be a potential neuroprotective response to amyloid exposure [49]. To advance AD drug discovery, there needs to be a shift in current research priorities to address newer concepts. This includes strategies that target the Ca2+ signaling disruptions which are imbedded in all the major features and risk factors for AD. Compounds that would normalize aberrant Ca2+ signaling could likely impede pathogenic cascades, and alter the course of the disease rather than merely delay the progression of cognitive symptoms. Financial Disclosure: JCR is employed by R D China, U.K Group, GlaxoSmithKline; BC and VGC are employed by Lyotropic Therapeutics.Figure 6. Dantrolene treatment reduces amyloid load in AD mice. (A) Representative 4G8-immunostained tissue from saline-treated (left) and dantrolene-treated (right) 6-month old TASTPM mice demonstrate an approximate 45 reduction in amyloid density with dantrolene treatment. (B) Averaged bar graphs show significant reduction in amyloid peptide staining in both the hippocampus (left) and cortex (right) in the dantrolenetreated mice compared to saline-treated mice. (C) Representative thioflavin S stained tissue from saline-treated (left) and dantrolene-treated (right) 6month old TASTPM mice show an approximate 42 reduction in amyloid density with drug treatment. (D) Averaged bar graphs show significant reduction in the density of dense core amyloid plaques in both the hippocampus (left) and cortex (right) in the dantrolene-treated mice (white bars) compared to saline-treated mice (black bars). * = p,0.05, scale bar = 250 mm, n = 4? mice per group. doi:10.1371/journal.pone.0052056.gNormalizing ER Ca2+ for AD TreatmentAuthor ContributionsConceived and designed the experiments: GES SC CB. Performed the experiments: SC CB MBM IG CS JK JW. Analyzed the data: SC CBMBM IG CS JK JW GES. Contributed reagents/materials/analysis tools: JCR VC BGC. Wrote the paper: GES SC CB.
Cardiovascular diseases, the leading cause of morbidity and mortality in industrialized countries are predominantly caused by atherosclerosis. This is an inflammatory disease, the result of a cascade of events in blood vessels, leading to remodelling of the arterial wall, and a subsequent reduction in lumen size. In recent years, traditional risk factors for atherosclerosis 18325633 (such as hypertension and hypercholesterolemia) have also been associated with decreased numbers and impaired function of circulating endothelial progenitor cells (EPCs.
