Emerging therapies for atopic dermatitis: TRPV1 antagonists.

Transient receptor potential (TRP) ion channels are important mediators of somatosensory signaling throughout the body. Our understanding of the contribution of TRPs to a multitude of cutaneous physiologic processes has grown substantially in the past decade. TRP cation channel subfamily V member 1 (TRPV1), one of the better-understood members of this large family of ion channels, affects multiple pathways involved in pruritus. Further, TRPV1 appears to play a role in maintaining skin barrier function. Together, these properties make TRPV1 a ripe target for new therapies in atopic dermatitis. Neurokinin antagonists may affect similar pathways and have been studied to this effect. Early trials data suggest that these therapies are safe, but assessment of their efficacy in atopic dermatitis is pending as we await publication of phase II and III clinical trials data.

Topical delivery of TRPsiRNA-loaded solid lipid nanoparticles confer reduced pain sensation via TRPV1 silencing, in rats.

Present work describes a novel composition for encapsulating TRPsiRNA (TRPV1-targeting siRNA) within lipid-matrix (4:1::glyceryl behnate:stearic acid) of SLNs, using suitably modified cold high-pressure homogenisation technique. Optimisation of the method and composition conducted using calf-thymus DNA (ctDNA), to avoid cost of TRPsiRNA molecules, resulted in small size (d50 = 50-100 nm) and high entrapment (77.22-98.5%). Complete masking of extreme negative charge of both ctDNA (-34.50 mV) and TRPsiRNA (-23.98 mV) upon encapsulation in SLNs without employing cationic components is reported herein for the first time. Diffusion-controlled release (90.17% at 72 h) from a rigid matrix shifted to porous matrix (at 24 h) due to solubilisation of stearic acid at 37 °C. Efficient in vitro (HEK293 T cells) and in vivo transfection and expression established the proof-of-concept. PEG600 as supporting-surfactant and vitrifying agent promoted small size, effective transfection and rupture of endosomal membrane to affect endosomal escape. Physiological efficacy in terms of significant increase (p < .0001) in paw-withdrawal-latency, following topical and intradermal application of TRPsiRNA-loaded SLNs, in rats, exposed to thermal hyperalgesia (145 and 182%, respectively) and capsaicin-induced pain (155 and 182%, respectively) indicate effective silencing of skin TRPV1. Significant decrease in intensity and duration (one-fifth) of capsaicin-induced nocifensive behaviour was also observed. Naked TRPsiRNA, however, did not show any effect.

Neuroprotective Effects of Drug-Induced Therapeutic Hypothermia in Central Nervous System Diseases.

OBJECTIVE: This review article focuses on the neuroprotective effect of drug-induced hypothermia in cerebrovascular diseases and discusses its related side effects. METHOD: A systematic literature search was performed using Pubmed and Embase electronic databases for a retrospective analysis. RESULTS: Experimental studies have shown that drug-induced hypothermia alleviates brain damage and plays a neuroprotective role, thereby reducing mortality and ameliorating neurological deficits. Therefore, drug-induced hypothermia has an important research value and is worth further consideration in the clinical setting. However, drug-induced hypothermia is also associated with side effects, such as ventricular tachycardia, ventricular fibrillation, suppressed immune function, infection, electrolyte imbalance, glucose metabolism disorders, and skeletal muscle tremor. Existing drugs with cooling effects belong to the following categories: (1) dopamine receptor agonists; (2) cannabis; (3) opioid receptors; (4) vanilloid receptors; (5) vasopressins (potent neurotensin receptor agonists); (6) thyroid drugs; (7) adenosine drugs; and (8) purine drugs.

Herpes Simplex Virus Vector-Mediated Gene Delivery of Poreless TRPV1 Channels Reduces Bladder Overactivity and Nociception in Rats.

Increased afferent excitability has been proposed as an important pathophysiology of interstitial cystitis/bladder pain syndrome (IC/BPS) and overactive bladder (OAB). In this study, we investigated whether herpes simplex virus (HSV) vectors encoding poreless TRPV1, in which the segment in C terminus of TRPV1 receptor is deleted, suppress bladder overactivity and pain behavior using a rat model of chemical cystitis. Replication-defective HSV vectors encoding poreless TRPV1 were injected into the bladder wall of adult female Sprague-Dawley rats. Additionally, recombinant HSV virus (vHG) vectors were injected as control. Cystometry (CMG) under urethane anesthesia was performed 1 week after viral injection to evaluate bladder overactivity induced by resiniferatoxin (RTx, a TRPV1 agonist). RTx-induced nociceptive behavior such as licking (lower abdominal licking) and freezing (motionless head-turning) was observed 2 weeks after viral injection. GFP expression in L4/L6/S1 dorsal root ganglia and the bladder as well as c-Fos-positive cells in the L6 spinal cord dorsal horn were also evaluated 2 weeks after viral injection. In CMG, the poreless TRPV1 vector-treated group showed a significantly smaller reduction in intercontraction intervals and voided volume after RTx infusion than the vHG-treated control group. The number of the RTx-induced freezing events was significantly decreased in the poreless TRPV1 group than in the vHG group, whereas there was no significant difference of the number of RTx-induced licking events between groups. The number of c-Fos-positive cells in the DCM and SPN regions of the L6 spinal dorsal horn was significantly smaller in the poreless TRPV1 group than in the vHG group. Our results indicated that HSV vector-mediated gene delivery of poreless TRPV1 had a therapeutic effect on TRPV1-mediated bladder overactivity and pain behavior. Thus, the HSV vector-mediated gene therapy targeting TRPV1 receptors could be a novel modality for the treatment of OAB and/or hypersensitive bladder disorders such as IC/BPS.

Transient receptor potential melastatin 8 channel inhibition potentiates the hypothermic response to transient receptor potential vanilloid 1 activation in the conscious mouse.

OBJECTIVES: Mild decrease in core temperature (therapeutic hypothermia) provides lasting neuroprotection following cardiac arrest or cerebral ischemia. However, current methods for producing therapeutic hypothermia trigger a cold-defense response that must be countered by sedatives, muscle paralytics, and mechanical ventilation. We aimed to determine methods for producing hypothermia in the conscious mouse by targeting two transient receptor potential channels involved in thermoregulation, two transient receptor potential (TRP) channels involved in thermoregulation, TRP vanilloid 1 (TRPV1) and TRP melastatin 8 (TRPM8). DESIGN: Controlled prospective animal study. SETTING: Research laboratory at academic medical center. SUBJECTS: Conscious unrestrained young and aged male mice. INTERVENTIONS: Mice were treated with the TRPV1 agonist dihydrocapsaicin, a TRPM8 inhibitor ("compound 5"), or their combination and the effects on core temperature (Tcore) were measured by implanted thermocouples and wireless transponders. MEASUREMENTS AND MAIN RESULTS: TRPV1 agonist dihydrocapsaicin produced a dose-dependent (2-4 mg/kg s.c.) drop in Tcore. A loading dose followed by continuous infusion of dihydrocapsaicin produced a rapid and prolonged (> 6 hr) drop of Tcore within the therapeutic range (32-34°C). The hypothermic effect of dihydrocapsaicin was augmented in aged mice and was not desensitized with repeated administration. TRPM8 inhibitor "compound 5" (20 mg/kg s.c.) augmented the drop in core temperature during cold exposure (8°C). When "compound 5" (30 mg/kg) was combined with dihydrocapsaicin (1.25-2.5 mg/kg), the drop in Tcore was amplified and prolonged. CONCLUSIONS: Activating warm receptors (TRPV1) produced rapid and lasting hypothermia in young and old mice. Furthermore, hypothermia induced by TRPV1 agonists was potentiated and prolonged by simultaneous inhibition of TRPM8.

Evaluation of novel vanilloid-based hemostatic agents in rats.

BACKGROUND: : Hemostatic dressings containing clotting factors, biodegradable matrices, and recombinant proteins have been developed to control bleeding for battlefield trauma and trauma in clinical settings. Our present study evaluates the use of a vanilloid compound in biodegradable hemostatic dressings in a rat model of trauma. METHODS: : Male Sprague-Dawley rats (n = 180) were randomly divided into treatment groups and control groups and subjected to a lethal groin injury at 30 degrees C and 37 degrees C. Treatment groups included hemostatic matrices consisting of Protosan and graded doses of 2.5%, 5%, 10%, 15%, and 20% of the vanilloid agonist CAP-305. Powder or bilayer patch formulations were applied to the injury site. The seal integrity was assessed by reperfusion of the animal to a minimum mean-arterial pressure (MAP) of 80 mm Hg and monitoring for 60 minutes postinjury. RESULTS: : Powder and patch formulations loaded with varying concentrations of CAP-305 were evaluated. Powders containing 2.5% to 20% drug by weight showed 40% to 80% seal rates at 37 degrees C (p < 0.0001), whereas no significant results were obtained at 30 degrees C compared with the control animals. Conversely, bilayer patches loaded with 5% to 20% drug exhibited a consistent 70% seal rate (p < 0.0001) at 37 degrees C and 70% to 90% seal rates (p < 0.0001) in hypothermic animals when compared with controls. CONCLUSIONS: : Our study demonstrates the efficacy of CAP-305 loaded hemostatic dressings in the rat model of lethal groin injury. This study provides relevant proof of concept for the development of vanilloid agonists as hemostatic agents.