Although blood–brain barrier (BBB) compromise is central to the etiology of diverse central nervous system (CNS) disorders, endothelial receptor proteins that control BBB function are poorly defined. The endothelial G-protein-coupled receptor (GPCR) Gpr124 has been reported to be required for normal forebrain angiogenesis and BBB function in mouse embryos, but the role of this receptor in adult animals is unknown. Here Gpr124 conditional knockout (CKO) in the endothelia of adult mice did not affect homeostatic BBB integrity, but resulted in BBB disruption and microvascular hemorrhage in mouse models of both ischemic stroke and glioblastoma, accompanied by reduced cerebrovascular canonical Wnt–β-catenin signaling. Constitutive activation of Wnt–β-catenin signaling fully corrected the BBB disruption and hemorrhage defects of Gpr124-CKO mice, with rescue of the endothelial gene tight junction, pericyte coverage and extracellular-matrix deficits. We thus identify Gpr124 as an endothelial GPCR specifically required for endothelial Wnt signaling and BBB integrity under pathological conditions in adult mice. This finding implicates Gpr124 as a potential therapeutic target for human CNS disorders characterized by BBB disruption.
Parkinson's disease (PD) is the second most common neurodegenerative disorder and prevalence increases with age. Normal physiological changes that occur during the aging process reflect the pathological characteristics of Parkinson's disease. It is also recognized that age related changes significantly interact with the pathological mechanisms that underlie the neurodegeneration in PD and perpetuate the disease process. Despite the fact that aging is considered to be a primary risk factor for developing PD, the use of aged animal models are still under-utilized in pre-clinical research, thus reducing the translatability of experimental findings. Here, we use a natural compound astaxanthin (AXT) with multiple biological activities to attenuate neurotoxicity in a mouse model of Parkinson's disease in both young and aged mice. We observed that AXT preserved neurons in the substantia nigra of both young and aged mice that were exposed to the MPTP neurotoxin. However, AXT was less efficacious in the aged animals, as AXT was not able to protect against the MPTP induced loss of tyrosine hydroxylase (TH) throughout the aged nigro-striatal circuit. This disparity in the neuroprotective effect of AXT suggests that aging is a critical factor to consider during the development of novel therapeutics for neurodegenerative diseases and should be more rigorously evaluated in preclinical models.
Background: Astaxanthin (AXT) is a natural carotenoid with diverse biological activities. Although it is best known as a potent antioxidant, recent work suggests additional mechanisms of action that have the potential to oppose the ongoing pathophysiology of Parkinson’s disease (PD). For example, AXT has a putative role in modulating microglial activity and preserving mitochondrial function, thereby implicating this compound as a neuroprotective agent. Both oxidative stress and inflammation are involved in the progression of many neurodegenerative diseases. Therefore, we examined the efficacy for AXT to reduced neurotoxicity in a toxic model of PD in mice. Methods: In this study, we used a 4-week dietary supplementation of algae derived AXT to reduce 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced dopaminergic cell death.Results: AXT treated mice were protected against the loss of tyrosine hydroxylase (TH) staining in the substantia nigra (SN) after MPTP exposure compared to the control diet. This effect of preserved TH immunoreactivity was also observed in the striatum. Furthermore, AXT administration was able to interrupt the neuroinflammatory process known to contribute to neurodegeneration in this model.Conclusions: We demonstrate that AXT neuroprotection was associated with attenuated microglial activation as indicated by reduced immunohistochemical detection of IBA-1 in the SN and striatum of AXT treated mice. Altogether, these studies suggest that AXT has neuroprotective property in the central nervous system against MPTP neurodegeneration.Keywords: Astaxanthin, Neuroprotection, Neurodegeneration, Neuroinflammation, Parkinson’s disease
DARPP-32, a dopamine- and adenosine 3',5'-cyclic monophosphate (cAMP)-regulated inhibitor of protein phosphatase-1, is highly colocalized with neuronal and nonneuronal D1-type receptors. DARPP-32 concentration is enriched in the renal outer medulla and in the medium-size spiny neurons of the brain. In the ascending limb of the loop of Henle, DARPP-32 is phosphorylated following stimulation by dopamine and other first messengers, and in this form inhibits the activity of the Na(+)-K(+)-adenosinetriphosphatase pump. For functional analysis of the DARPP-32 promoter in the kidney, we characterized the murine gene. There are two groups of transcription start sites utilized in the brain, but the proximal set appears to be preferentially used in the kidney. In four of four lines of mice carrying a DARPP-32/lacZ transgene with 2.1 kb of 5'-flanking DNA, adult kidney lacZ transgene expression mimicked that of endogenous DARPP-32. There was no ectopic expression in peripheral organs. We conclude that the sequences necessary for direction of DARPP-32 expression to the medullary thick ascending limb are contained within this 2.1-kb fragment.
BackgroundThe superiority of nipple‐sparing mastectomy (NSM) on breast aesthetics and patient‐reported outcomes has previously been demonstrated. Despite 42.4% of adults in the United States being considered obese, obesity has been considered a contraindication to NSM due to concerns for nipple areolar complex (NAC) malposition or ischemic complications. This report investigates the feasibility and safety of a staged surgical approach to NSM with immediate microsurgical breast reconstruction in the high‐risk obese population.MethodsOnly patients with a body mass index (BMI) of >30 kg/m2 who underwent bilateral mastopexy or breast reduction for correction of ptosis or macromastia (stage 1), respectively, followed by bilateral prophylactic NSM with immediate microsurgical breast reconstruction with free abdominal flaps (stage 2) were included in the analysis. Patient demographics and surgical outcomes were analyzed.ResultsFifteen patients with high‐risk genetic mutations for breast cancer with a mean age and BMI of 41.3 years and 35.0 kg/m2, respectively, underwent bilateral staged NSM with immediate microsurgical breast reconstruction (30 breast reconstructions). At a mean follow‐up of 15.7 months, complications were encountered following stage 2 only and included mastectomy skin necrosis (5 breasts [16.7%]), NAC necrosis (2 breasts [6.7%]), and abdominal seroma (1 patient [6.7%]) all of which were considered minor and neither required surgical intervention nor admission.ConclusionsImplementation of a staged approach permits NAC preservation in obese patients who present for prophylactic mastectomy and immediate microsurgical reconstruction.
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