Blood nerve barrier permeability enables nerve targeting of circulating nanoparticles in experimental autoimmune neuritis.

Guillain-Barré syndrome (GBS) is a devastating autoimmune disease of the peripheral nervous system (PNS) with limited treatment options. Several studies have shown attenuation of the well-characterized GBS preclinical experimental autoimmune neuritis (EAN) model with systemically administered therapeutic compounds via anti-inflammatory or immunomodulatory mechanisms. Despite this, clinical advancement of these findings is limited by dosing that is not translatable to humans or is associated with off-target and toxic effects.

Simvastatin-Loaded Chitosan-Functionalized PLGA Nanoparticles: Characterization and Use in Intimal Hyperplasia Therapy.

: Statins have beneficial pleiotropic effects, including reducing intimal hyperplasia (IH), but off-target effects remain a concern. Here, we tested the hypothesis that chitosan-functionalized polymeric nanoparticles (NPs) loaded with simvastatin (SL-cNPs) would (1) readily associate with endothelial cells (ECs) and vascular smooth muscle cells (VSMCs); (2) affect EC and VSMC function; and (3) reduce IH compared to systemic simvastatin. : Human aortic ECs and VSMCs were cultured with fluorescently labeled SL-cNPs.

Chitosan/poly(lactic-co-glycolic)acid Nanoparticle Formulations with Finely-Tuned Size Distributions for Enhanced Mucoadhesion.

Non-parenteral drug delivery systems using biomaterials have advantages over traditional parenteral strategies. For ocular and intranasal delivery, nanoparticulate systems must bind to and permeate through mucosal epithelium and other biological barriers. The incorporation of mucoadhesive and permeation-enhancing biomaterials such as chitosan facilitate this, but tend to increase the size and polydispersity of the nanoparticles, making practical optimization and implementation of mucoadhesive nanoparticle formulations a challenge.

Optimization of critical parameters for coating of polymeric nanoparticles with plasma membrane vesicles by sonication.

Top-down functionalization of nanoparticles with cellular membranes imparts nanoparticles with enhanced bio-interfacing capabilities. Initial methods for membrane coating involved physical co-extrusion of nanoparticles and membrane vesicles through a porous membrane; however, recent works employ sonication as the disruptive force to reform membranes around the surface of nanoparticles. Although sonication is widely used, there remains a paucity of information on the effects of sonication variables on coating efficiency, leading to inconsistent membrane coating across studies.

Poly(lactic-co-glycolic acid) Nanoparticles Encapsulating the Prenylated Flavonoid, Xanthohumol, Protect Corneal Epithelial Cells from Dry Eye Disease-Associated Oxidative Stress.

Oxidative stress is a known contributor to the progression of dry eye disease pathophysiology, and previous studies have shown that antioxidant intervention is a promising therapeutic approach to reduce the disease burden and slow disease progression. In this study, we evaluated the pharmacological efficacy of the naturally occurring prenylated chalconoid, xanthohumol, in preclinical models for dry eye disease. Xanthohumol acts by promoting the transcription of phase II antioxidant enzymes.

Strategies for Targeted Delivery to the Peripheral Nerve.

Delivery of compounds to the peripheral nervous system has the potential to be used as a treatment for a broad range of conditions and applications, including neuropathic pain, regional anesthesia, traumatic nerve injury, and inherited and inflammatory neuropathies. However, efficient delivery of therapeutic doses can be difficult to achieve due to peripheral neuroanatomy and the restrictiveness of the blood-nerve barrier. Depending on the underlying integrity of the blood-nerve barrier in the application at hand, several strategies can be employed to navigate the peripheral nerve architecture and facilitate targeted delivery to the peripheral nerve.

Attenuation of experimental autoimmune neuritis with locally administered lovastatin-encapsulating poly(lactic-co-glycolic) acid nanoparticles.

Acute inflammatory demyelinating polyneuropathy (AIDP) is an aggressive antibody- and T-cell-mediated variant of Guillain-Barré Syndrome (GBS), a prominent and debilitating autoimmune disorder of the peripheral nervous system. Despite advancements in clinical management, treatment of patients with AIDP/GBS and its chronic variant CIDP remains palliative and relies on the use of non-specific immunemodulating therapies. Our laboratory has previously reported that therapeutic administration of statins safely attenuates the clinical severity of experimental autoimmune neuritis (EAN), a well-characterized animal model of AIDP/GBS, by restricting the migration of autoreactive leukocytes across peripheral nerve microvascular endoneurial endothelial cells that form the blood-nerve barrier.

Rho GTPase signaling promotes constitutive expression and release of TGF-β2 by human trabecular meshwork cells.

Elevated intraocular pressure (IOP) is causally implicated in the pathophysiology of primary open-angle glaucoma (POAG). The molecular mechanisms responsible for elevated IOP remain elusive, but may involve aberrant expression and signaling of transforming growth factor (TGF)-β2 within the trabecular meshwork (TM). Consistent with previously published studies, we show here that exogenous addition of TGF-β2 to cultured porcine anterior segments significantly attenuates outflow facility in a time-dependent manner.

Forced Exercise Preconditioning Attenuates Experimental Autoimmune Neuritis by Altering Th1 Lymphocyte Composition and Egress.

A short-term exposure to moderately intense physical exercise affords a novel measure of protection against autoimmune-mediated peripheral nerve injury. Here, we investigated the mechanism by which forced exercise attenuates the development and progression of experimental autoimmune neuritis (EAN), an established animal model of Guillain-Barré syndrome. Adult male Lewis rats remained sedentary (control) or were preconditioned with forced exercise (1.

Novel role of Cdc42 and RalA GTPases in TNF-α mediated secretion of CCL2.

Transendothelial migration of autoreactive leukocytes into peripheral nerves is an early pathological hallmark of acute inflammatory demyelinating polyneuropathy (AIDP), a North American and European variant of Guillain-Barré Syndrome. Whereas the clinical management of AIDP is currently limited to non-selective immune modulating therapies, recent experimental studies support selective targeting of leukocyte trafficking as a promising alternative therapeutic strategy. Here, using a combination of targeted siRNA knockdown and pharmacological inhibitors, we report a novel role of both Cdc42 and RalA GTPases in facilitating TNF-α mediated CCL2 trafficking and release from immortalized rat peripheral nerve microvascular endoneurial endothelial cells.

Cdc42 GTPases facilitate TNF-α-mediated secretion of CCL2 from peripheral nerve microvascular endoneurial endothelial cells.

Trafficking of autoreactive leukocytes across the blood-nerve barrier and into peripheral nerves is an early pathological hallmark of Guillain-Barré syndrome (GBS). Tumor necrosis factor-α (TNF-α), a proinflammatory cytokine, promotes transendothelial migration by upregulating endothelial expression of inflammatory mediators, including CCL2, a chemokine implicated in GBS. We sought to determine the mechanism by which TNF-α induces expression and secretion of CCL2 from peripheral nerve microvascular endoneurial endothelial cells (PNMECs).

Tumour necrosis factor α enhances CCL2 and ICAM-1 expression in peripheral nerve microvascular endoneurial endothelial cells.

Recruitment and trafficking of autoreactive leucocytes across the BNB (blood-nerve barrier) is an early pathological insult in GBS (Guillain-Barré syndrome), an aggressive autoimmune disorder of the PNS (peripheral nervous system). Whereas the aetiology and pathogenesis of GBS remain unclear, pro-inflammatory cytokines, including TNFα (tumour necrosis factor α), are reported to be elevated early in the course of GBS and may initiate nerve injury by activating the BNB. Previously, we reported that disrupting leucocyte trafficking in vivo therapeutically attenuates the course of an established animal model of GBS.

Transforming growth factor-β2 induces synthesis and secretion of endothelin-1 in human trabecular meshwork cells.

Purpose: Analysis of aqueous humor from patients with primary open-angle glaucoma (POAG) revealed marked increases in the content of endothelin-1 (ET-1) and transforming growth factor-beta (TGF-β). We determined the consequences of TGF-β signaling on ET-1 expression and secretion by human trabecular meshwork (TM) cells.

Methods: Primary or transformed (NTM5 and GTM3) human TM cells conditioned in serum-free media were incubated in the absence or presence of TGF-β1 or -β2.