Dabigatran reduces thrombin-induced neuroinflammation and AD markers in vitro: Therapeutic relevance for Alzheimer's disease.

Background: Vascular risk factors such as atherosclerosis, diabetes, and elevated homocysteine levels are strongly correlated with onset of Alzheimer's disease (AD). Emerging evidence indicates that blood coagulation protein thrombin is associated with vascular and non-vascular risk factors of AD. Here, we examined the effect of thrombin and its direct inhibitor dabigatran on key mediators of neuro-inflammation and AD pathology in the retinoic acid (RA)-differentiated human neuroblastoma cell line SH-SY5Y.

High Glucose and Hypoxia-Mediated Damage to Human Brain Microvessel Endothelial Cells Induces an Altered, Pro-Inflammatory Phenotype in BV-2 Microglia In Vitro.

Diabetes is strongly linked to the development of Alzheimer's disease (AD), though the mechanisms for this enhanced risk are unclear. Because vascular inflammation is a consistent feature of both diabetes and AD, the cerebral microcirculation could be a key target for the effects of diabetes in the brain. The goal of this study is to explore whether brain endothelial cells, injured by diabetes-related insults, glucose and hypoxia, can affect inflammatory and activation processes in microglia in vitro.

Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD.

Autophagic dysregulation has been suggested in a broad range of neurodegenerative diseases including age-related macular degeneration (AMD). To test whether the autophagy pathway plays a critical role to protect retinal pigmented epithelial (RPE) cells against oxidative stress, we exposed ARPE-19 and primary cultured human RPE cells to both acute (3 and 24 h) and chronic (14 d) oxidative stress and monitored autophagy by western blot, PCR, and autophagosome counts in the presence or absence of autophagy modulators. Acute oxidative stress led to a marked increase in autophagy in the RPE, whereas autophagy was reduced under chronic oxidative stress.

The 5HT1a receptor agonist 8-Oh DPAT induces protection from lipofuscin accumulation and oxidative stress in the retinal pigment epithelium.

Age-related macular degeneration (AMD), a major cause of blindness in the elderly, is associated with oxidative stress, lipofuscin accumulation and retinal degeneration. The aim of this study was to determine if a 5-HT(1A) receptor agonist can reduce lipofuscin accumulation, reduce oxidative damage and prevent retinal cell loss both in vitro and in vivo. Autophagy-derived and photoreceptor outer segment (POS)-derived lipofuscin formation was assessed using FACS analysis and confocal microscopy in cultured retinal pigment epithelial (RPE) cells in the presence or absence of the 5-HT(1A) receptor agonist, 8-OH DPAT.

Autophagy in the retina: a potential role in age-related macular degeneration.

Age-related macular degeneration (AMD) is associated with multiple genetic and cellular defects which lead to a common endpoint, retinal degeneration. Aging and oxidative stress, significant features in the pathogenesis of AMD, are associated with an increase in damaged intracellular organelles and defective autophagy flux in a range of age-related and neurodegenerative diseases. Autophagy is a key process in maintenance of cellular homeostasis that serves to remove dysfunctional organelles and proteins.

Involvement of PGE2 and PGDH but not COX-2 in thrombin-induced cortical neuron apoptosis.

The pathways that contribute to thrombin-induced neuron death have been incompletely defined. Induction of cyclooxygenase 2 (COX-2), the enzyme that catalyzes the first step in prostaglandin synthesis, promotes neuronal injury. PGE2, a downstream product of COX-2 metabolism, is neurotoxic in vitro and in vivo, and is thought to be the bioactive mediator responsible for COX-2 neurotoxicity.

Cyclin C and cyclin dependent kinases 1, 2 and 3 in thrombin-induced neuronal cell cycle progression and apoptosis.

The extent to which neurons proceed into the cell cycle and the mechanisms whereby cell cycle re-entry leads to apoptosis vary in response to agonists. We previously showed upregulation of early G1 regulators in thrombin-treated neurons yet neurons did not proceed to S phase but to apoptosis. The objective of this study is to explore mechanisms which might prevent S phase entry and promote apoptosis in thrombin-treated neurons.

PACAP38 protects rat cortical neurons against the neurotoxicity evoked by sodium nitroprusside and thrombin.

Pituitary adenylate cyclase-activating polypeptide (PACAP) 38 is a multifunctional anti-inflammatory and anti-apoptotic neuropeptide widely distributed in the nervous system. The objective of this study is to determine whether PACAP38 is neuroprotective against sodium nitroprusside (SNP) and thrombin, two mechanistically distinct neurotoxic agents. Treatment of primary cortical neuronal cultures with 1 mM SNP for 4 h causes neuronal cell death that is significantly reduced by 100 nM PACAP38.

IL-8 induces expression of matrix metalloproteinases, cell cycle and pro-apoptotic proteins, and cell death in cultured neurons.

Neuronal cell loss is a critical feature of age-related neurodegenerative diseases such as Alzheimer's disease (AD). In the AD brain, a marked increase in pro-inflammatory cytokines and chemokines, including IL-8, has been documented. The objective of this study was to determine the effect of IL-8 on cell viability and expression of neurotoxic, apoptotic, and cell cycle proteins in cultured neurons.

Cyclin D1, cdk4, and Bim are involved in thrombin-induced apoptosis in cultured cortical neurons.

Thrombin, a multifunctional serine protease, is neurotoxic in vitro and in vivo. Thrombin has been shown to be increased in Alzheimer's disease (AD) and other neuropathological conditions and could be a mediator of pathological neuronal cell death in the brain. The mechanisms of thrombin-induced neuronal cell death are incompletely understood.