An official website of the United States government
Combining hemodynamic and morphological measurements from male, female, and ovariectomized female pulmonary arterial hypertension (PAH) rats revealed distinct adaptation mechanisms despite similar pressure overload. Males showed the most diastolic stiffening. Ovariectomized females had enhanced myocyte contractility and calcium transient upregulation. Ovary-intact females primarily responded with hypertrophy, experiencing milder passive myocardial stiffening and no changes in myocyte shortening. These findings suggest potential sex-specific pathways in right ventricular (RV) adaptation to PAH, with implications for targeted interventions.
more »
« less
Increasing Progenitor Cell Proliferation in the Sub-Ventricular Zone: A Therapeutic Treatment for Progressive Multiple Sclerosis?
Introduction: The purpose of this study was to determine if pharmacological treatmentcould increase progenitor cell proliferation in the Sub-ventricular Zone of aged rats. Previous workhad shown that increasing progenitor cell proliferation in this region correlated well (R2=0.78; p=0.0007) with functional recovery in a damaged corpus callosum (white matter tract), suggesting thatprogenitor cell proliferation results in oligodendrocytes in this region. Methods: 10 month old male and female Sprague Dawley rats were fed the drugs for 30 days in cookiedough, then immunocytochemistry was performed on coronal brain sections, using Ki67 labeling todetermine progenitor cell proliferation. Results: Female rats showed low endogenous (control) progenitor cell proliferation, significantly differentfrom male rats (P<0.0001), at this age. Ascorbic Acid (20 mg/kg, daily for 30 days) increasedprogenitor cell proliferation overall, but maintained the innate gender difference in stem cell proliferation(P=0.001). Prozac (5 mg/kg, daily for 30 days) increased progenitor cell proliferation for femalesbut decreased stem cell proliferation for males, again showing a gender difference (P<0.0001).Simvastatin (1 mg/kg for 30 days) also increased progenitor cell proliferation in females and decreasedprogenitor cell proliferation in males, leading to a significant gender difference. Discussion: The three drug combinations (fluoxetine, simvastatin, and ascorbic acid, patent #9,254,281) led to ~ 4 fold increase in progenitor cell proliferation in females, while male progenitorcell proliferation was highest with 50 mg/kg ascorbic acid. However, the ascorbic acid increase in proliferationappears to be only on the sides of the ventricles, which is not the region that normally givesrise to oligodendrocytes. Conclusion: There are innate gender differences in progenitor cell proliferation at the Sub-VentricularZone at middle age in rats, possibly due to the loss of estrogen in females. We also see notable genderdifferences in progenitor cell proliferation in the Sub ventricular Zone in response to common drugs,such as fluoxetine, simvastatin and Vitamin C (ascorbic acid).
more »
« less
- Award ID(s):
- 1742339
- PAR ID:
- 10228273
- Date Published:
- Journal Name:
- Recent Patents on Drug Delivery & Formulation
- Volume:
- 14
- Issue:
- 3
- ISSN:
- 1872-2113
- Page Range / eLocation ID:
- 233 to 241
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
While male mate choice has received sparse attention in comparison to female choice, it occurs often in insects. In addition, male insects may preferentially allocate sperm and ejaculate in response to female quality. Previous research indicates that male Bicyclus anynana butterflies can learn mate preference through prior exposure to females, though naïve males mate randomly. It is unclear whether this preference learning may also influence male sperm and ejaculate allocation after mate selection, or whether males have cryptic mate preference for female wing patterns independent of preference learning. Here we test whether B. anynana males adjust their sperm and ejaculate allocation in response to a learned preference. We also assess whether males exhibit an innate cryptic preference and adjust their sperm and ejaculate in response to female wing pattern. We compared number of eggs laid by females and spermatophore (male butterfly ejaculate) weight in four no-choice treatments: naïve male butterflies (having no prior exposure to females), paired with a 2 or 0-spot female, and experienced male butterflies (having a previous three-hour interaction with a 0-spot female), paired with a 2 or 0-spot female. All females used were naturally 2-spot females, 0-spot females had artificially blocked spots. We found that 0-spot females laid significantly more eggs than 2-spot females, independent of male experience. There was no effect of female phenotype or male experience on spermatophore weight. Our findings suggest that male B. anynana have an innate cryptic preference for 0-spot females, which has been shown in other studies to only be seen as a pre-copulatory preference when enhanced by early experience.more » « less
-
Background.Safe sensory-selective local anesthetics would be a major advance in the management of acute and chronic pain. Here we describe the sensory-selective local anesthetic properties and the toxicity profile of a known metabolite of amino-amide local anesthetics,2',6'-pipecolylxylidine (PPX). Methods.PPX was synthesized and made into its hydrochloride salt. PPX or ropivacaine (ROP) were injected at the sciatic nerve or intrathecally in rats, who then underwent modified hotplate (sensory) testing and weight-bearing (motor) testing. Rats injected with PPX or ROP were assessed for clinical toxicity endpoints. Conduction blockade was studied with single-unit recordings in mice. Biocompatibility was assessed histologically. Results.In male rats, sciatic sensory and motor block from 15 mM ROP lasted ~150 min; sensory nerve block from 30 mM PPX lasted 67.4 ± 17.4 min without motor block. Addition of chemical permeation enhancers to 30 mM PPX abolished sensory selectivity. Intrathecal 15 mM ROP produced sensory and motor block lasting ~15 min; sensory block from 30 mM PPX lasted 24.8 ± 8.7 min without motor block; repeated injection caused continuous sensory-selective block. In female rats, sciatic nerve blocks with ROP were similar to blocks in males, while blocks with PPX were sensory-selective but higher PPX concentrations were required. Ex vivo, 1.5 mM ROP caused reversible block of Aδ and C-fibers; 15 mM PPX blocked Aδ- but not C-fibers. Systemic 39.0 ± 1.8 mg/kg ROP caused severe clinical toxicity; 75.3 ± 3.2 mg/kg PPX caused none. Tissue reaction to PPX was benign, comparable to that of ROP. Conclusions.PPX provides sensory-selective local and neuraxial anesthesia with a good safety profile. The sensory selectivity may be attributable to the particular hydrophilic-hydrophobic balance of PPX.more » « less
-
Summary Patients with neurocognitive disorders often battle sleep disturbances. Kynurenic acid is a tryptophan metabolite of the kynurenine pathway implicated in the pathology of these illnesses. Modest increases in kynurenic acid, an antagonist at glutamatergic and cholinergic receptors, result in cognitive impairments and sleep dysfunction. We explored the hypothesis that inhibition of the kynurenic acid synthesising enzyme, kynurenine aminotransferase II, may alleviate sleep disturbances. At the start of the light phase, adult male and female Wistar rats received systemic injections of either: (i) vehicle; (ii) kynurenine (100 mg kg−1; i.p.); (iii) the kynurenine aminotransferase II inhibitor, PF‐04859989 (30 mg kg−1; s.c.); or (iv) PF‐04859989 and kynurenine in combination. Kynurenine and kynurenic acid levels were evaluated in the plasma and brain. Separate animals were implanted with electroencephalogram and electromyogram telemetry devices to record polysomnography, and evaluate the vigilance states wake, rapid eye movement sleep and non‐rapid eye movement sleep following each treatment. Kynurenine challenge increased brain kynurenic acid and resulted in reduced rapid eye movement sleep duration, non‐rapid eye movement sleep delta power and sleep spindles. PF‐04859989 reduced brain kynurenic acid formation when given prior to kynurenine, prevented disturbances in rapid eye movement sleep and sleep spindles, and enhanced non‐rapid eye movement sleep. Our findings suggest that reducing kynurenic acid in conditions where the kynurenine pathway is activated may serve as a potential strategy for improving sleep dynamics.more » « less
-
Kratom is derived from the leaves of a plant (Mitragyna speciosa) native to Southeast Asia that has been consumed for its complex stimulant-like effects at low doses, opiate-like effects at high doses, to treat mood related issues like anxiety or depression, or to help ameliorate opioid withdrawal symptoms. However, the neural mechanisms of its major psychoactive alkaloids, mitragynine (MG) and 7-hydroxymitragynine (7-HMG), are still not clear. Given that the effects of kratom are often compared to drugs with abuse liabilities, the current study examined the effects of MG and 7-HMG on reward-related neurotransmission. Fixed potential amperometry was used to quantify stimulation-evoked phasic dopamine release in the nucleus accumbens (NAc) of anesthetized male and female mice before and after MG (1, 15, or 30 mg/kg i.p.), 7-HMG (0.5, 1, or 2 mg/kg i.p.), or vehicle. MG reduced dopamine release over the recording period (90 min) in a dose dependent manner, and the low dose of MG significantly increased dopamine autoreceptor functioning in males. Both sexes responded similarly to 7-HMG with the low dose of 7-HMG increasing dopamine release while the high dose decreased dopamine release. 7-HMG did not alter dopamine autoreceptor functioning for either sex. Neither MG nor 7-HMG altered the clearance rate of stimulation-evoked dopamine. Findings suggest that these kratom alkaloids do alter dopamine functioning, although potentially not in a way consistent with classic drugs of abuse. Further investigation of the neural mechanisms of kratom’s alkaloids will provide crucial and urgent insight into their therapeutic uses or potential abuse liability.more » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.2174/1872211314999201117130123
