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Impact of Intraventricular Human Adipose-Derived Stem Cells Transplantation with Pregnenolone Treatment on Remyelination of Corpus Callosum in A Rat Model of Multiple Sclerosis.

OBJECTIVE: Multiple sclerosis (MS) is known as a nerve tissue disorder, which causes demyelination of central nervous system (CNS) fibers. Cell-based treatment is a novel strategy for the treatment of demyelinating diseases such as MS. Adipose-derived stem cells (ADSCs) have neuroprotective and neuroregenerative effects and pregnenolone as a neurosteroid has remarkable roles in neurogenesis. We intend to examine the impact of intraventricular transplantation of human ADSCs and systemic injection of pregnenolone on the remyelination of a rat model cuprizone-induced demyelination. MATERIALS AND

TRPM3 in Brain (Patho)Physiology.

Already for centuries, humankind is driven to understand the physiological and pathological mechanisms that occur in our brains. Today, we know that ion channels play an essential role in the regulation of neural processes and control many functions of the central nervous system. Ion channels present a diverse group of membrane-spanning proteins that allow ions to penetrate the insulating cell membrane upon opening of their channel pores. This regulated ion permeation results in different electrical and chemical signals that are necessary to maintain physiological excitatory and inhibitory pro

Pharmacological properties of TRPM3 isoforms are determined by the length of the pore loop.

BACKGROUND AND PURPOSE: Transient receptor potential melastatin 3 (TRPM3) is a non-selective cation channel that plays a pivotal role in the peripheral nervous system as a transducer of painful heat signals. Alternative splicing gives rise to several TRPM3 variants. The functional consequences of these splice isoforms are poorly understood. Here, the pharmacological properties of TRPM3 variants arising from alternative splicing in the pore-forming region were compared. EXPERIMENTAL APPROACH: Calcium microfluorimetry and patch clamp recordings were used to compare the properties of heterologou

Positive allosteric modulation of GABAA receptors attenuates high blood pressure in Schlager hypertensive mice.

OBJECTIVE: Blood pressure high Schlager (BPH/2J) mice have neurogenic hypertension associated with differences in hypothalamic GABAA receptors compared with their normotensive counterparts (BPN/3J). Allopregnanolone is an endogenous neurosteroid reduced in chronic stress, and when administered, decreases anxiety by positive allosteric modulation of GABAA receptors. METHODS: To determine if allopregnanolone could be a viable therapeutic for neurogenic hypertension, male BPH/2J (n = 6-7) and BPN/3J (n = 8-9) mice were equipped with radiotelemetry probes to compare cardiovascular variables befor

Pregnenolone treatment reduces severity of negative symptoms in recent-onset schizophrenia: an 8-week, double-blind, randomized add-on two-center trial.

AIMS: Management of recent-onset schizophrenia (SZ) and schizoaffective disorder (SA) is challenging owing to frequent insufficient response to antipsychotic agents. This study aimed to test the efficacy and safety of the neurosteroid pregnenolone in patients with recent-onset SZ/SA. METHODS: Sixty out- and inpatients who met DSM-IV criteria for SZ/SA, with suboptimal response to antipsychotics were recruited for an 8-week, double-blind, randomized, placebo-controlled, two-center add-on trial, that was conducted between 2008 and 2011. Participants were randomized to receive either pregnenolon

Membrane-initiated estradiol actions mediate structural plasticity and reproduction.

Over the years, our ideas about estrogen signaling have greatly expanded. In addition to estradiol having direct nuclear actions that mediate transcription and translation, more recent experiments have demonstrated membrane-initiated signaling. Both direct nuclear and estradiol membrane signaling can be mediated by the classical estrogen receptors, ERα and ERβ, which are two of the numerous putative membrane estrogen receptors. Thus far, however, only ERα has been shown to play a prominent role in regulating female reproduction and sexual behavior. Because ERα is a ligand-gated transcription f

Regeneration in a degenerating brain: potential of allopregnanolone as a neuroregenerative agent.

Confronting the efficacy of a regenerative therapeutic is the degenerative environment that is characterized by neuronal loss, physical plague and glial scar barriers and inflammation. But perhaps more fundamental from a regenerative perspective, are changes in the biochemical milieu of steroid and peptide growth factors, cytokines and neurotransmitter systems. Data from multiple levels of analysis indicate that gonadal steroid hormones and their metabolites can promote neural health whereas their decline or absence are associated with decline in neural health and increased risk of neurodegene

Behavioral sensitization to ethanol is modulated by environmental conditions, but is not associated with cross-sensitization to allopregnanolone or pentobarbital in DBA/2J mice.

RATIONALE: The ability of ethanol to facilitate GABA(A) receptor-mediated transmission may result in GABA(A) receptor alterations during repeated ethanol administration, and lead to dynamic behavioral changes, including sensitization to the locomotor stimulant effect of ethanol. Since alterations in GABA(A) receptors are likely to alter sensitivity to GABAergic drugs such as 3alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone) and pentobarbital, we determined whether enhanced sensitivity to ethanol was associated with enhanced sensitivity (cross-sensitization) to these drugs. Two procedures

Chronic pregnenolone effects in normal humans: attenuation of benzodiazepine-induced sedation.

Pregnenolone is the major steroid precursor in humans. It is also a "neurosteroid" and possesses intrinsic behavioral and brain effects in animals, affecting the GABA(A) and other receptors. In two preliminary studies, we sought to characterize its tolerability and psychotropic effects in humans. In Study 1, 17 normal volunteers received pregnenolone and placebo for 4 weeks each (15 mg PO per day x2 weeks followed by 30 mg PO per day x2 weeks, vs. placebo x4 weeks) in a within-subject, double-blind, cross-over design, with a 4 week drug-free washout period separating the two arms. Subjects' be

Cortical gamma-aminobutyric acid levels across the menstrual cycle in healthy women and those with premenstrual dysphoric disorder: a proton magnetic resonance spectroscopy study.

BACKGROUND: There is increasing support for the hypothesis that gonadal steroids involved in the regulation of the human menstrual cycle modulate gamma-aminobutyric acid (GABA) neuronal function. This study tests the hypothesis that cortical GABA neuronal function, reflected in brain GABA concentrations, fluctuates across the menstrual cycle in healthy women and those with premenstrual dysphoric disorder (PMDD) and that a menstrual cycle phase-dependent abnormality in brain GABA concentrations in women diagnosed as having PMDD would reflect altered central response to circulating gonadal and n

Pharmacological modulation of GABA(A) receptor-mediated postsynaptic potentials in the CA1 region of the rat hippocampus.

It is unclear whether GABA(A) receptor-mediated hyperpolarizing and depolarizing synaptic potentials (IPSP(A)s and DPSP(A)s, respectively) are evoked by (a) the same populations of GABAergic interneurones and (b) exhibit similar regulation by allosteric modulators of GABA(A) receptor function. We have attempted to address these questions by investigating the effects of (a) known agonists for presynaptic receptors on GABAergic terminals, and (b) a range of GABA(A) receptor ligands, on each response. The GABA uptake inhibitor NNC 05-711 (10 microM) enhanced whereas bicuculline (10 microM) inhibi

Estradiol benzoate potentiates neuroactive steroids' effects on pain sensitivity.

Progesterone (P), its metabolites, and other neuroactive steroids alter pain thresholds consistent with their efficacies at modulating gamma-aminobutyric acid (GABAA) receptor complexes. We investigated whether estradiol benzoate (EB) potentiates low dosages of neuroactive steroids' effects on pain. Subcutaneous EB (10 micrograms) or sesame oil vehicle was administered to ovariectomized Long-Evans rats (n = 40) 48 h before intracerebroventricular (ICV) infusion of a neuroactive steroid (0.0, 0.1, 0.3, or 0.5 micrograms) in cyclodextrin vehicle. Neuroactive steroids (listed from greatest to lea

New Antidepressant Development in the Treatment of Depression.

Major depressive disorder (MDD) continues to pose a major therapeutic challenge due to its clinical heterogeneity. This chapter looks at the … odulators (NAMs). In addition, gamma-aminobutyric acid (GABA) modulation has gained attention, with neurosteroids such as zurolone (approved for postpartum depression [PPD]) representing a new therapeutic approach. Other new strategies target the opioid system, particularly kappa-opioid receptor (KOR) antagonism, whose role in the treatment of anhedonia and dep …

Milestone review: GABA, from chemistry, conformations, ionotropic receptors, modulators, epilepsy, flavonoids, and stress to neuro-nutraceuticals.

Arising out of a PhD project more than 50 years ago to synthesise analogues of the neurotransmitter GABA, a series of new chemical entities … ges in GABA receptors in the brain that may be because of changes in endogenous modulators, such as neurosteroids and corticosteroids. GABA also occurs naturally in the diet leading to studies of the effects of oral GABA on brain function. This finding has resulted in studies of GABA and related neurochemicals as neuro-nutraceuticals. GABA systems in the gut mi …

Совместное использование внутриутробного метилпреднизолона и Аллопрегнанолона: повторное изучение методов борьбы с воспламенением и ремиелионированием в мюриновой модели множественного склероза.

Множественный склероз (MS) представляет собой демиелинизирующее, нейровоспалительное, прогрессивное заболевание, которое оказывает серьезное воздействие на здоровье молодых людей. Нейроинфламмация (НИ) и обезвоживание, а также их взаимодействие являются ключевыми терапевтическими целями для остановки или замедления развития заболеваний. Для повышения своей эффективности путем обеспечения прямого доступа к центральной нервной системе (СНС) можно было бы совместно использовать такие вредные стероцидные противовоспалительные препараты, как метилпреднизолон (МП) и ремиелионирующие нейроиды, такие,

Совпадение в аннотации оригинала
BACKGROUND: Multiple sclerosis (MS) is a demyelinating, neuroinflammatory, progressive disease that severely affects human health of young a … ression. Potent steroidal anti-inflammatory drugs such as methylprednisolone (MP) and remyelinating neurosteroids such as allopregnanolone (ALLO) could be co-administered intranasally to enhance their efficacy by providing direct access to the central nervous system (CNS). METHODS: The individual and combined effects of MP and ALLO to control the clinical scor …

Efficacy and safety of anti-inflammatory agents in treatment of psychotic disorders - A comprehensive systematic review and meta-analysis.

OBJECTIVE: Antipsychotic effects of immunomodulating drugs have been suggested; however, a thorough, comprehensive meta-analysis on the effe … monoclonal antibodies (k = 15), or drugs with potential anti-inflammatory properties (k = 55), e.g. neurosteroids, N-acetyl cysteine, estrogens, fatty acids, statins, and glitazones. Antipsychotics plus anti-inflammatory treatment, compared to antipsychotics plus placebo, was associated with a PANSS scale MD improvement of -4.57 (95%CI = -5.93 to -3.20) points, …

Survey of Veterinarians Using a Novel Physical Compression Squeeze Procedure in the Management of Neonatal Maladjustment Syndrome in Foals.

Horses are a precocious species that must accomplish several milestones that are critical to survival in the immediate post-birth period for … the NMS syndrome with the persistence of high concentrations of in utero neuromodulating hormones (neurosteroids) in the postnatal period. Anecdotal evidence demonstrated that a novel physical compression (squeeze) method that applies 20 min of sustained pressure to the thorax of some neonatal foals with this syndrome might rapidly hasten recovery. This survey …

The biological basis of injury and neuroprotection in the fetal and neonatal brain.

A compromised intrauterine environment that delivers low levels of oxygen and/or nutrients, or is infected or inflammatory, can result in fe … ntinues; we discuss neuroprotective agents (erythropoietin, N-acetyl cysteine, melatonin, creatine, neurosteroids) which we have trialed in appropriate animal models. The possibility of combining hypothermia with such agents or growth factors is now being considered. A deeper understanding of causal pathways in brain injury is essential for the development of e …

Associations of endocannabinoids and related lipid mediators with depressive symptoms during perimenopause.

BACKGROUND: Perimenopause is associated with increased vulnerability to depressive symptoms, partly driven by fluctuations in gonadal steroid hormones, particularly estradiol. The neurobiological mechanisms underlying this vulnerability remain unclear. Alterations in the endocannabinoid system (ECS) during perimenopause may represent a mechanistic pathway contributing to mood disturbance, given its role in emotion regulation and stress responsivity, as well as its modulation by estradiol. However, circulating endocannabinoids have not been examined in relation to perimenopausal depressive symp

The Association of Vitamin D, Nerve Growth Factor (NGF), Brain-Derived Neurotrophic Factor (BDNF), and Glial Cell-Derived Neurotrophic Factor (GDNF) with Development in Children.

BACKGROUND: Short stature remains a global problem and is associated with vitamin D status. Vitamin D is also a neurosteroid with regard to neurotrophic factors but its role in development is unclear. Therefore, this study analyzed the relationships between vitamin D, NGF, GDNF, and BDNF and developmental status in children with a history of short stature (<2 years). METHODS: This research is a prospective cross-sectional study conducted in March 2022. The vitamin D, NGF, GDNF, and BDNF levels were measured in stored biological materials from children aged 2-4 years, and their Ages and Stages