scholarly journals CSF Secretion Is Not Altered by NKCC1 Nor TRPV4 Antagonism in Healthy Rats

2021 ◽  
Vol 11 (9) ◽  
pp. 1117
Author(s):  
Steven W Bothwell ◽  
Daniel Omileke ◽  
Adjanie Patabendige ◽  
Neil J Spratt
Keyword(s):  
Transient Receptor Potential ◽  
Therapeutic Potential ◽  
Receptor Potential ◽  
Positive Control ◽  
Secretion Rate ◽  
Cerebral Aqueduct ◽  
Transient Receptor Potential Vanilloid ◽  
Supporting Evidence ◽  
Male Wistar Rats ◽  
Secretion Rates

Background: Cerebrospinal fluid (CSF) secretion can be targeted to reduce elevated intracranial pressure (ICP). Sodium-potassium-chloride cotransporter 1 (NKCC1) antagonism is used clinically. However, supporting evidence is limited. The transient receptor potential vanilloid-4 (TRPV4) channel may also regulate CSF secretion and ICP elevation. We investigated whether antagonism of these proteins reduces CSF secretion. Methods: We quantified CSF secretion rates in male Wistar rats. The cerebral aqueduct was blocked with viscous mineral oil, and a lateral ventricle was cannulated. Secretion rate was measured at baseline and after antagonist administration. Acetazolamide was administered as a positive control to confirm changes in CSF secretion rates. Results: Neither NKCC1, nor TRPV4 antagonism altered CSF secretion rate from baseline, n = 3, t(2) = 1.14, p = 0.37, and n = 4, t(3) = 0.58, p = 0.6, respectively. Acetazolamide reduced CSF secretion by ~50% across all groups, n = 7, t(6) = 4.294, p = 0.005. Conclusions: Acute antagonism of NKCC1 and TRPV4 proteins at the choroid plexus does not reduce CSF secretion in healthy rats. Further investigation of protein changes and antagonism should be explored in neurological disease where increased CSF secretion and ICP are observed before discounting the therapeutic potential of protein antagonism at these sites.

scholarly journals Cannabidiol as a Potential Treatment for Anxiety and Mood Disorders: Molecular Targets and Epigenetic Insights from Preclinical Research

2021 ◽  
Vol 22 (4) ◽  
pp. 1863
Author(s):  
Philippe A. Melas ◽  
Maria Scherma ◽  
Walter Fratta ◽  
Carlo Cifani ◽  
Paola Fadda
Keyword(s):  
Mood Disorders ◽  
Cannabinoid Receptors ◽  
Transient Receptor Potential ◽  
Therapeutic Potential ◽  
Molecular Targets ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Preclinical Research ◽  
Neuropsychiatric Diseases ◽  
Transient Receptor

Cannabidiol (CBD) is the most abundant non-psychoactive component of cannabis; it displays a very low affinity for cannabinoid receptors, facilitates endocannabinoid signaling by inhibiting the hydrolysis of anandamide, and stimulates both transient receptor potential vanilloid 1 and 2 and serotonin type 1A receptors. Since CBD interacts with a wide variety of molecular targets in the brain, its therapeutic potential has been investigated in a number of neuropsychiatric diseases, including anxiety and mood disorders. Specifically, CBD has received growing attention due to its anxiolytic and antidepressant properties. As a consequence, and given its safety profile, CBD is considered a promising new agent in the treatment of anxiety and mood disorders. However, the exact molecular mechanism of action of CBD still remains unknown. In the present preclinical review, we provide a summary of animal-based studies that support the use of CBD as an anxiolytic- and antidepressant-like compound. Next, we describe neuropharmacological evidence that links the molecular pharmacology of CBD to its behavioral effects. Finally, by taking into consideration the effects of CBD on DNA methylation, histone modifications, and microRNAs, we elaborate on the putative role of epigenetic mechanisms in mediating CBD’s therapeutic outcomes.

Proteinase-Activated Receptor-4 (PAR4) Activation Leads to Sensitization of Rat Joint Primary Afferents Via a Bradykinin B2 Receptor-Dependent Mechanism

2010 ◽  
Vol 103 (1) ◽  
pp. 155-163 ◽  
Author(s):  
Fiona A. Russell ◽  
Victoria E. Veldhoen ◽  
Dmitri Tchitchkan ◽  
Jason J. McDougall
Keyword(s):  
Firing Rate ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Receptor Activation ◽  
Primary Afferents ◽  
Knee Joints ◽  
Transient Receptor Potential Vanilloid ◽  
Mechanical Stimuli ◽  
Male Wistar Rats ◽  
Normal Rat

The G-protein-linked receptor, proteinase-activated receptor-4 (PAR4) is activated by proteinases released into the joint during inflammation. It is unclear whether PAR4 has a pro- or anti-nociceptive effect and whether it directly affects nerve activity. In this study, we examined the expression of PAR4 in joints and dorsal root ganglion (DRG) neurons and whether activation of PAR4 has an effect on nociception in normal rat knee joints. Electrophysiological recordings were made from joint primary afferents in male Wistar rats during both nonnoxious and noxious rotations of the knee. Afferent firing rate was recorded for 15 min post close intra-arterial injection of 10−9–10−5 mol of the PAR4 activating peptide, AYPGKF-NH2, or the inactive peptide, YAPGKF-NH2 (100 μl bolus). Rats were either naive or pretreated with the selective PAR4 antagonist, pepducin P4pal-10, the transient receptor potential vanilloid-1 (TRPV1) antagonist, SB366791, or the bradykinin B2 receptor antagonist, HOE140. Immunofluorescence experiments showed extensive PAR4 expression in the knee joint and in sensory neurons projecting from the joint. AYPGKF-NH2 significantly increased joint afferent firing during nonnoxious and noxious rotation of the knee. The inactive control peptide, YAPGKF-NH2 was without effect. Systemic pretreatment with the PAR4 antagonist, pepducin P4pal-10, inhibited the AYPGKF-NH2-induced increase in firing rate. Pretreatment with HOE140, but not SB366791, also blocked this increase in firing rate. These data reveal that in normal rat knee joints, PAR4 activation increases joint primary afferent activity in response to mechanical stimuli. This PAR4-induced sensitization is TRPV1-independent but involves B2 receptor activation, suggesting a role for kinins in this process.

scholarly journals Effects of Chronic Administration of Capsaicin on Biomarkers of Kidney Injury in Male Wistar Rats with Experimental Diabetes

Molecules ◽  
2018 ◽  
Vol 24 (1) ◽  
pp. 36 ◽  
Author(s):  
Mónica Ríos-Silva ◽  
Rubén Santos-Álvarez ◽  
Xóchitl Trujillo ◽  
Rosa Cárdenas-María ◽  
Marisa López-Zamudio ◽  
...  
Keyword(s):  
Wistar Rats ◽  
Transient Receptor Potential ◽  
Experimental Diabetes ◽  
Kidney Injury ◽  
Receptor Potential ◽  
Chronic Administration ◽  
Diabetic Rats ◽  
Transient Receptor Potential Vanilloid ◽  
Healthy Controls ◽  
Male Wistar Rats

Capsaicin is an agonist of the transient receptor potential vanilloid type 1 (TRPV1) channel, which has been related to the pathophysiology of kidney disease secondary to diabetes. This study aimed to evaluate the chronic effect of capsaicin administration on biomarkers of kidney injury in an experimental rat model of diabetes. Male Wistar rats were assigned to four groups: (1) healthy controls without diabetes (CON), (2) healthy controls plus capsaicin at 1 mg/kg/day (CON + CAPS), (3) experimental diabetes without capsaicin (DM), and (4) experimental diabetes plus capsaicin at 1 mg/kg/day (DM + CAPS). For each group, 24-h urine samples were collected to determine diuresis, albumin, cystatin C, β2 microglobulin, epidermal growth factor (EGF), alpha (1)-acid glycoprotein, and neutrophil gelatinase-associated lipocalin (NAG-L). Blood samples were drawn to measure fasting glucose. After 8 weeks, the CON + CAPS and DM + CAPS groups showed increased diuresis compared to the CON and DM groups, but the difference was significant only in the DM + CAPS group. The two-way ANOVA only showed a statistically significant effect of CAPS on the urinary EGF levels, as well as a tendency to have a significant effect in the urinary NAG-L levels. The EGF levels decreased in both CAPS-treated groups, but the change was only significant in the CON + CAPS group vs. CON group; and the NAG-L levels were lower in both CAPS-treated groups. These results show that capsaicin had a diuretic effect in healthy and diabetic rats; additionally, it increased the urinary EGF levels and tended to decrease the urinary NAG-L levels.

scholarly journals TRPV1-mediated protection against endotoxin-induced hypotension and mortality in rats

2008 ◽  
Vol 294 (5) ◽  
pp. R1517-R1523 ◽  
Author(s):  
Youping Wang ◽  
Martin Novotný ◽  
Veronika Quaiserová-Mocko ◽  
Greg M. Swain ◽  
Donna H. Wang
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Protective Role ◽  
Sensory Nerves ◽  
Transient Receptor Potential Vanilloid ◽  
Induced Hypotension ◽  
Trpv1 Receptors ◽  
Male Wistar Rats ◽  
Neurokinin 1 ◽  
Transient Receptor

This study was designed to test the hypothesis that the transient receptor potential vanilloid type 1 (TRPV1) channel, expressed primarily in sensory nerves, and substance P (SP), released by sensory nerves, play a protective role against lipopolysaccharide (LPS)-induced hypotension. LPS (10 mg/kg iv) elicited tachycardia and hypotension in anesthetized male Wistar rats, which peaked at 10 min and gradually recovered 1 h after the injection. Blockade of TRPV1 with its selective antagonist capsazepine (CAPZ, 3 mg/kg iv) impaired recovery given that the fall in mean arterial pressure (MAP) was greater 1 h after CAPZ plus LPS injections compared with LPS injection alone (45 ± 5 vs. 25 ± 4 mmHg, P < 0.05). Blockade of the neurokinin 1 (NK1) receptor with its selective antagonists RP-67580 (5 mg/kg iv) or L-733,060 (4 mg/kg iv) prevented recovery, considering that falls in MAP were not different 1 h after injections of NK1 antagonists plus LPS from their peak decreases (66 ± 9 vs. 74 ± 5 mmHg or 60 ± 7 vs. 69 ± 3 mmHg, respectively, P > 0.05). LPS increased plasma SP, norepinephrine (NE), and epinephrine (Epi) levels compared with vehicles, and the increases in plasma SP, NE, and Epi were significantly inhibited by CAPZ or RP-67580. The survival rate at 24 or 48 h after LPS injection (20 mg/kg ip) was lower in conscious rats pretreated with CAPZ or RP-67580 compared with rats treated with LPS alone ( P < 0.05). Thus our results show that the TRPV1, possibly via triggering release of SP which activates the NK1 and stimulates the sympathetic axis, plays a protective role against endotoxin-induced hypotension and mortality, suggesting that TRPV1 receptors are essential in protecting vital organ perfusion and survival during the endotoxic condition.

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