Use of a Self-Delivering Anti-CCL3 FANA Oligonucleotide as an Innovative Approach to Target Inflammation after Spinal Cord Injury.

Secondary damage after spinal cord injury (SCI) occurs because of a sequence of events after the initial injury, including exacerbated inflammation that contributes to increased lesion size and poor locomotor recovery. Thus, mitigating secondary damage is critical to preserve neural tissue and improve neurologic outcome. In this work, we examined the therapeutic potential of a novel antisense oligonucleotide (ASO) with special chemical modifications [2'-deoxy-2-fluoro-D-arabinonucleic acid (FANA) ASO] for specifically inhibiting an inflammatory molecule in the injured spinal cord.

CCL3 contributes to secondary damage after spinal cord injury.

Background: Secondary damage after spinal cord injury (SCI) is characterized by a cascade of events including hemorrhage, apoptosis, oxidative stress, and inflammation which increase the lesion size which can influence the functional impairment. Thus, identifying specific mechanisms attributed to secondary injury is critical in minimizing tissue damage and improving neurological outcome. In this work, we are investigating the role of CCL3 (macrophage inflammatory protein 1-α, MIP-1α), a chemokine involved in the recruitment of inflammatory cells, which plays an important role in inflammatory conditions of the central and peripheral nervous system.

Differential expression of ryanodine receptor isoforms after spinal cord injury.

Ryanodine receptors (RyRs) are highly conductive intracellular Ca release channels and are widely expressed in many tissues, including the central nervous system. RyRs have been implicated in intracellular Ca overload which can drive secondary damage following traumatic injury to the spinal cord (SCI), but the spatiotemporal expression of the three isoforms of RyRs (RyR1-3) after SCI remains unknown. Here, we analyzed the gene and protein expression of RyR isoforms in the murine lumbar dorsal root ganglion (DRG) and the spinal cord lesion site at 1, 2 and 7 d after a mild contusion SCI.

Intracellular calcium release through IPR or RyR contributes to secondary axonal degeneration.

Severed CNS axons often retract or dieback away from the injury site and fail to regenerate. The precise mechanisms underlying acute axonal dieback and secondary axonal degeneration remain poorly understood. Here we investigate the role of Ca store mediated intra-axonal Ca release in acute axonal dieback and secondary axonal degeneration.

The toll-like receptor 2 agonist Pam3CSK4 is neuroprotective after spinal cord injury.

Microglia/macrophage activation and recruitment following spinal cord injury (SCI) is associated with both detrimental and reparative functions. Stimulation of the innate immune receptor Toll-like receptor-2 (TLR2) has shown to be beneficial following SCI, and it increases axonal regeneration following optic nerve crush. However, the mechanism(s) remain unclear.

Plasminogen Activator Inhibitor-1 Antagonist TM5484 Attenuates Demyelination and Axonal Degeneration in a Mice Model of Multiple Sclerosis.

Multiple sclerosis (MS) is characterized by inflammatory demyelination and deposition of fibrinogen in the central nervous system (CNS). Elevated levels of a critical inhibitor of the mammalian fibrinolitic system, plasminogen activator inhibitor 1 (PAI-1) have been demonstrated in human and animal models of MS. In experimental studies that resemble neuroinflammatory disease, PAI-1 deficient mice display preserved neurological structure and function compared to wild type mice, suggesting a link between the fibrinolytic pathway and MS.

A novel antidiabetic therapy: free fatty acid receptors as potential drug target.

Excessive dietary intake of fat is strongly involved in the development of type 2 diabetes (T2D). Free fatty acids (FFAs), which are provided from dietary fat, are not only important nutrients, but also act as signaling molecules and stimulate key biological functions. Recent physiological and pharmacological studies have shown that several G-protein coupled receptors, such as FFAR1-4, are receptors for FFAs.

RAS inhibition attenuates cognitive impairment by reducing blood- brain barrier permeability in hypertensive subjects.

Recent studies have suggested that blood-brain barrier (BBB) abnormalities are present from an early stage in patients exhibiting mild symptoms of cognitive impairment during the development of hypertension. There is also growing body of evidence suggesting the potential role of the renin-angiotensin system (RAS) in the pathogenesis of small-vessel disease and cognitive impairment. However, the specific contribution of the RAS to BBB disruption and cognitive impairment remains unclear.

Angiotensin-converting enzyme inhibitor does not suppress renal angiotensin II levels in angiotensin I-infused rats.

Angiotensin II (Ang II) infusion into rats elevates local angiotensin II levels through an AT1 receptor-dependent pathway in the kidney. We examined whether treatment with an angiotensin-converting enzyme (ACE) inhibitor, temocapril, or an AT1-receptor blocker, olmesartan, prevented elevation of Ang II levels in the kidney of angiotensin I (Ang I)-infused rats. Rats were infused with Ang I (100 ng/min) and treated with temocapril (30 mg/kg per day, n = 10) or olmesartan (10 mg/kg per day, n = 9) for 4 weeks.

Effects of angiotensin II AT₁-receptor blockade on high fat diet-induced vascular oxidative stress and endothelial dysfunction in Dahl salt-sensitive rats.

We examined the effects of angiotensin II AT₁-receptor blockade with olmesartan on high fat (HF) diet-induced vascular oxidative stress and endothelial dysfunction in normal salt (NS) diet-fed Dahl salt-sensitive (DSS) rats. Treatment with NS + HF diet (32% crude fat, 0.3% NaCl) for 20 weeks significantly increased blood pressure in DSS rats.

Therapeutic effects of postischemic treatment with hypotensive doses of an angiotensin II receptor blocker on transient focal cerebral ischemia.

Background: Neurovascular protection against cerebral ischemia is not consistently observed with a postischemia hypotensive dose of candesartan. The aim of this study was to determine the levels of brain angiotensin II after reperfusion and the efficacy and therapeutic time window of postischemic treatments with hypotensive doses of candesartan for the treatment of cerebral ischemia.

Method: Occlusions of the right middle cerebral artery (60 min) followed by reperfusion were performed using the thread method under halothane anesthesia in Sprague-Dawley (SD) rats.

Angiotensin II induces human astrocyte senescence through reactive oxygen species production.

Angiotensin II (Ang II)-induced astrocyte senescence may be involved in cerebral ischemic injury and age-associated neurodegenerative disease. This study was conducted to determine the roles of reactive oxygen species production in Ang II-induced cellular senescence in cultured human astrocytes. Human astrocytes were stimulated with Ang II either with or without an angiotensin type 1 receptor blocker, CV11974, or an antioxidant, tempol.

Blockade of AT1 receptors protects the blood-brain barrier and improves cognition in Dahl salt-sensitive hypertensive rats.

Background: The present study tested the hypothesis that inappropriate activation of the brain renin-angiotensin system (RAS) contributes to the pathogenesis of blood-brain barrier (BBB) disruption and cognitive impairment during development of salt-dependent hypertension. Effects of an angiotensin II (AngII) type-1 receptor blocker (ARB), at a dose that did not reduce blood pressure, were also examined.

Methods: Dahl salt-sensitive (DSS) rats at 6 weeks of age were assigned to three groups: low-salt diet (DSS/L; 0.

Mechanical stretch potentiates angiotensin II-induced proliferation in spontaneously hypertensive rat vascular smooth muscle cells.

Angiotensin II (AngII) stimulates vascular smooth muscle cell (VSMC) proliferation; however, the effect of AngII on cell proliferation in the presence of mechanical force is not clear. We investigated the mechanism of AngII-induced cell proliferation mediated by mechanical stretch in VSMCs of both normotensive and hypertensive rats. VSMCs obtained from the thoracic aortas of 8-week-old Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were stretched by a Flex culture system.

Regression of superficial glomerular podocyte injury in type 2 diabetic rats with overt albuminuria: effect of angiotensin II blockade.

Objective: Clinical studies indicate that the remission, regression or both of nephrotic-range albuminuria are exerted by angiotensin II receptor blockers (ARBs) in diabetes. The current study was performed to test the hypothesis that these effects of ARBs are associated with regression of glomerular podocyte injury.

Methods: We examined the effects of an ARB, olmesartan, on glomerular podocyte injury in type 2 diabetic Otsuka-Long-Evans-Tokushima-Fatty rats with overt albuminuria.

Systemic candesartan reduces brain angiotensin II via downregulation of brain renin-angiotensin system.

The renin-angiotensin system has an important function in the regulation of blood pressure as well as in pathophysiological processes in the central nervous system. We examined the effects of the angiotensin receptor blocker candesartan (10 mg kg(-1) per day, p.o.

Possible contribution of the non-proteolytic activation of prorenin to the development of insulin resistance in fructose-fed rats.

Recent studies have shown that blocking non-proteolytically activated prorenin with a decoy peptide for the handle region of the prorenin prosegment (HRP) inhibits the development of microvascular complications in diabetic animals. In the present study, we investigated whether non-proteolytic activation of prorenin contributes to the development of fructose-induced insulin resistance. Rats were fed a standard diet (n = 10), a 60% high fructose diet (n = 16), or a high fructose diet + HRP (0.