Suppression of Harmaline Tremor by Activation of an Extrasynaptic GABA Receptor: Implications for Essential Tremor.

Background: Metabolic imaging has revealed excessive cerebellar activity in essential tremor patients. Golgi cells control cerebellar activity by releasing gamma-aminobutyric acid (GABA) onto synaptic and extrasynaptic receptors on cerebellar granule cells. We postulated that the extrasynaptic GABA receptor-specific agonist THIP (gaboxadol; 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) would suppress tremor in the harmaline model of essential tremor and, since cerebellar extrasynaptic receptors contain 6 and subunits, would fail to do so in mice lacking either subunit.

Autophagy Modulation by Lanthionine Ketimine Ethyl Ester Improves Long-Term Outcome after Central Fluid Percussion Injury in the Mouse.

Diffuse axonal injury is recognized as a progressive and long-term consequence of traumatic brain injury. Axonal injury can have sustained negative consequences on neuronal functions such as anterograde and retrograde transport and cellular processes such as autophagy that depend on cytoarchitecture and axon integrity. These changes can lead to somatic atrophy and an inability to repair and promote plasticity.

Oral TNFα Modulation Alters Neutrophil Infiltration, Improves Cognition and Diminishes Tau and Amyloid Pathology in the 3xTgAD Mouse Model.

Cytokines such as TNFα can polarize microglia/macrophages into different neuroinflammatory types. Skewing of the phenotype towards a cytotoxic state is thought to impair phagocytosis and has been described in Alzheimer's Disease (AD). Neuroinflammation can be perpetuated by a cycle of increasing cytokine production and maintenance of a polarized activation state that contributes to AD progression.

A cell-penetrating ester of the neural metabolite lanthionine ketimine stimulates autophagy through the mTORC1 pathway: Evidence for a mechanism of action with pharmacological implications for neurodegenerative pathologies.

Autophagy is a fundamental cellular recycling process vulnerable to compromise in neurodegeneration. We now report that a cell-penetrating neurotrophic and neuroprotective derivative of the central nervous system (CNS) metabolite, lanthionine ketimine (LK), stimulates autophagy in RG2 glioma and SH-SY5Y neuroblastoma cells at concentrations within or below pharmacological levels reported in previous mouse studies. Autophagy stimulation was evidenced by increased lipidation of microtubule-associated protein 1 light chain 3 (LC3) both in the absence and presence of bafilomycin-A1 which discriminates between effects on autophagic flux versus blockage of autophagy clearance.

A derivative of the brain metabolite lanthionine ketimine improves cognition and diminishes pathology in the 3 × Tg-AD mouse model of Alzheimer disease.

Lanthionine ketimine ([LK] 3,4-dihydro-2H-1,4-thiazine-3,5-dicarboxylic acid) is the archetype for a family of naturally occurring brain sulfur amino acid metabolites, the physiologic function of which is unknown. Lanthionine ketimine and its synthetic derivatives have recently demonstrated neurotrophic, neuroprotective, and antineuroinflammatory properties in vitro through a proposed mechanism involving the microtubule-associated protein collapsin response mediator protein 2. Therefore, studies were undertaken to test the effects of a bioavailable LK ester in the 3 × Tg-AD mouse model of Alzheimer disease.

Early intervention with a small molecule inhibitor for tumor necrosis factor-α prevents cognitive deficits in a triple transgenic mouse model of Alzheimer's disease.

Background: Chronic neuroinflammation is an important component of Alzheimer's disease and could contribute to neuronal dysfunction, injury and loss that lead to disease progression. Multiple clinical studies implicate tumor necrosis factor-α as an inflammatory mediator of neurodegeneration in patients with Alzheimer's because of elevated levels of this cytokine in the cerebrospinal fluid, hippocampus and cortex. Current Alzheimer's disease interventions are symptomatic treatments with limited efficacy that do not address etiology.

TGF beta2-induced changes in LRP-1/T beta R-V and the impact on lysosomal A beta uptake and neurotoxicity.

Numerous studies suggest a central role for the low-density lipoprotein receptor-related protein/transforming growth factor beta receptor V in Alzheimer's Disease. We continue our investigation of a ligand for this receptor, transforming growth factor beta2, which is also implicated in Alzheimer Disease pathogenesis, but whose mechanism(s) remain elusive. Confocal imaging reveals that transforming growth factor beta2 rapidly targets amyloid beta peptide to the lysosomal compartment in cortical neurons and induces cell death.

Uric acid stimulates vascular smooth muscle cell proliferation and oxidative stress via the vascular renin-angiotensin system.

Background: Plasma uric acid has been associated with hypertension in a variety of disorders, and has been shown to be predictive of hypertension. The mechanistic role of uric acid in the development of hypertension is not known however.

Method: We tested the hypothesis that uric acid stimulates vascular smooth muscle cell (VSMC) proliferation and oxidative stress by stimulating the vascular renin-angiotensin system (RAS).

Vascular Angiotensin type 1 receptor expression is associated with vascular dysfunction, oxidative stress and inflammation in fructose-fed rats.

This study determined whether or not oxidative stress and vascular dysfunction in fructose-induced hyperinsulinemic rats are associated with activation of the vascular renin-angiotensin system (RAS). Four groups of rats were used. CONT rats were fed normal rat chow, CONT+CAP were fed normal rat chow and given 500 mg/L captopril in their drinking water, fructose-fed rats (FFR) were fed a high-fructose diet and FFR+CAP were fed the high-fructose diet plus captopril in water.

Dietary fish oil prevents vascular dysfunction and oxidative stress in hyperinsulinemic rats.

Background: Fish oil has been shown to improve blood pressure (BP) in some disease states by an unknown mechanism. We tested the ability of fish oil to prevent vascular dysfunction in fructose-fed rats, a model of insulin resistance and hypertension.

Methods: Rats were placed on three diets: 1) regular rat diet (control); 2) diet containing 60% fructose (FFR); or 3) diet containing 60% fructose and 4.

Insulin stimulates endogenous angiotensin II production via a mitogen-activated protein kinase pathway in vascular smooth muscle cells.

Objective: The present study was designed to determine the effects of insulin on cytosolic angiotensin II production and proliferation in cultured rat vascular smooth muscle cells.

Design And Methods: Vascular smooth muscle cells were incubated with insulin for 48 h. Cytosolic angiotensin I and II were determined by radioimmunoassays of purified cell homogenates.

The role of the sympathetic nervous system in linking obesity with hypertension in white versus black Americans.

Several previous studies confirmed that obesity is a major risk factor for the development of cardiovascular diseases, including hypertension. A large number of clinical studies considered the role of the sympathetic nervous system in linking obesity with hypertension, and there is substantial evidence that human obesity is characterized by defects in sympathetic cardiovascular control. The association of obesity with hypertension has been well documented in most racial, ethnic, and socioeconomic groups.