The United States is entering its fourth decade of the opioid epidemic with no clear end in sight. At the center of the epidemic is an increase in opioid use disorder (OUD), a complex condition ...encompassing physical addiction, psychological comorbidities, and socioeconomic and legal travails associated with the misuse and abuse of opioids. Existing behavioral and medication-assisted therapies show limited efficacy as they are hampered by lack of access, strict regimens, and failure to fully address the non-pharmacological aspects of the disease. A growing body of research has indicated the potential of hallucinogens to efficaciously and expeditiously treat addictions, including OUD, by a novel combination of pharmacology, neuroplasticity, and psychological mechanisms. Nonetheless, research into these compounds has been hindered due to legal, social, and safety concerns. This review will examine the preclinical and clinical evidence that psychoplastogens, such as ibogaine, ketamine, and classic psychedelics, may offer a unique, holistic alternative for the treatment of OUD while acknowledging that further research is needed to establish long-term efficacy along with proper safety and ethical guidelines.
Neuroinflammation has been postulated to be a key factor in the pathogenesis of major depressive disorder (MDD). With this is mind, there has been a wave of research looking into pro-inflammatory ...mediators as potential biomarkers for MDD. One such mediator is the acute phase protein, C-reactive protein (CRP). While several studies have investigated the potential of CRP as a biomarker for MDD, the results have been inconsistent. One explanation for the lack of consistent findings may be that the high-sensitivity CRP tests utilized in these studies only measure the pentameric isoform of CRP (pCRP). Recent research, however, has indicated that the monomeric isoform of CRP (mCRP) is responsible for the pro-inflammatory function of CRP, while pCRP is weakly anti-inflammatory. The objective of this minireview is to re-examine the evidence of CRP involvement in MDD with a view of mCRP as a potential biomarker.
Abstract
From the earliest days of the coronavirus disease 2019 (COVID-19) pandemic, there have been reports of significant neurological and psychological symptoms following Severe Acute Respiratory ...Syndrome Coronavirus 2 (SARS-CoV-2) infection. This narrative review is designed to examine the potential psychoneuroendocrine pathogenic mechanisms by which SARS-CoV-2 elicits psychiatric sequelae as well as to posit potential pharmacologic strategies to address and reverse these pathologies. Following a brief overview of neurological and psychological sequelae from previous viral pandemics, we address mechanisms by which SARS-CoV-2 could enter or otherwise elicit changes in the CNS. We then examine the hypothesis that COVID-19–induced psychiatric disorders result from challenges to the neuroendocrine system, in particular the hypothalamic-pituitary-adrenal stress axis and monoamine synthesis, physiological mechanisms that are only further enhanced by the pandemic-induced social environment of fear, isolation, and socioeconomic pressure. Finally, we evaluate several FDA-approved therapeutics in the context of COVID-19–induced psychoneuroendocrine disorders.
C-reactive protein (CRP) is an acute phase, predominantly hepatically synthesized protein, secreted in response to cytokine signaling at sites of tissue injury or infection with the physiological ...function of acute pro-inflammatory response. Historically, CRP has been classified as a mediator of the innate immune system, acting as a pattern recognition receptor for phosphocholine-containing ligands. For decades, CRP was envisioned as a single, non-glycosylated, multi-subunit protein arranged non-covalently in cyclic symmetry around a central void. Over the past few years, however, CRP has been shown to exist in at least three distinct isoforms: 1.) a pentamer of five identical globular subunits (pCRP), 2.) a modified monomer (mCRP) resulting from a conformational change when subunits are dissociated from the pentamer, and 3.) a transitional isoform where the pentamer remains intact but is partially changed to express mCRP structural characteristics (referred to as pCRP* or mCRP
). The conversion of pCRP into mCRP can occur spontaneously and is observed under commonly used experimental conditions. In careful consideration of experimental design used in published reports of
pro- and anti-inflammatory CRP bioactivities, we herein provide an interpretation of how distinctive CRP isoforms may have affected reported results. We argue that pro-inflammatory amplification mechanisms are consistent with the biofunction of mCRP, while weak anti-inflammatory mechanisms are consistent with pCRP. The interplay of each CRP isoform with specific immune cells (platelets, neutrophils, monocytes, endothelial cells, natural killer cells) and mechanisms of the innate immune system (complement), as well as differences in mCRP and pCRP ligand recognition and effector functions are discussed. This review will serve as a revised understanding of the structure-function relationship between CRP isoforms as related to inflammation and innate immunity mechanisms.
Abstract
Endothelin-B receptor agonist, IRL-1620, provides significant neuroprotection following cerebral ischemia in rats. Whether this neuroprotection is due to inhibition of apoptosis is unknown. ...IRL-1620-treated rats following permanent middle cerebral artery occlusion (MCAO) showed significant improvement in neurological and motor functions along with a decrease in infarct volume at 24 h (−81.3%) and day 7 (−73.0%) compared to vehicle group. Cerebral blood flow (CBF) significantly improved in IRL-1620-treated animals compared to vehicle by day 7 post MCAO. IRL-1620-treated rats showed an increase in phospho-Akt and decrease in Bad level 7 h post-occlusion compared to vehicle, while Akt and Bad expression was similar in cerebral hemispheres at 24 h post-MCAO. The phospho-Bad level was lower in vehicle- but not in IRL-1620-treated rats at 24 h. Anti-apoptotic Bcl-2 expression decreased, while pro-apoptotic Bax expression increased in vehicle-treated MCAO rats, these changes were attenuated (P < 0.01) by IRL-1620. Mitochondrial membrane-bound Bax intensity significantly decreased in IRL-1620 compared to vehicle-treated MCAO rats. IRL-1620 treatment reduced (P < 0.001) the number of TUNEL-positive cells compared to vehicle at 24 h and day 7 post MCAO. The results demonstrate that IRL-1620 is neuroprotective and attenuates neural damage following cerebral ischemia in rats by increasing CBF and reducing apoptosis.
Neonatal HIE is associated with high morbidity and mortality. Current research, is focused on developing alternative treatments to therapeutic hypothermia for treatment of HIE. The endocannabinoid ...system is known to be influential in neuronal protection. Activation of brain CB2 receptors, has been shown to reduce inflammatory markers and decrease infarct volume in adult cerebral ischemic models.
Rat pups were divided into six groups: 1-Placebo; 2-JWH133; 3-HIE + Placebo; 4-HIE + JWH133; 5-HIE + Hypothermia + Placebo; and 6-HIE + Hypothermia + JWH133. HIE was induced in in groups 3-6 by right carotid ligation on postnatal day 7 followed by placement in a hypoxic chamber. Pups in groups 5 and 6 were treated with hypothermia. Western blot analysis was used to analyze brain tissue for acute inflammatory markers (IL-6, TNFα, MIP1α, and RANTES), immunoregulatory cytokines (TGFβ and IL-10), and CB2 receptor expression. DNA fragmentation in the brains of pups was determined via TUNEL staining post HIE.
The combination of JWH133 and hypothermia significantly reduced tumor necrosis factor α (TNFα) (-57.7%,
= 0.0072) and macrophage inflammatory protein 1α (MIP1α) (-50.0%,
= 0.0211) as compared to placebo. DNA fragmentation was also significantly reduced, with 6.9 ± 1.4% TUNEL+ cells in HIE+JWH133 and 12.9 ± 2.2% in HIE+Hypothermia + JWH133 vs. 16.6 ± 1.9% in HIE alone. No significant difference was noted between groups for the expression of interleukins 6 and 10, RANTES, or TGFβ. After 8 h, CB2 receptor expression increased nearly 2-fold in the HIE and HIE + JWH133 groups (+214%,
= 0.0102 and +198%,
= 0.0209, respectively) over placebo with no significant change in the hypothermia groups. By 24 h post HIE, CB2 receptor expression was elevated over five times that of placebo in the HIE (
< 0.0001) and HIE + JWH133 (
= 0.0002) groups, whereas hypothermia treatment maintained expression similar to that of placebo animals.
These results indicate that the combination of CB2 agonist and hypothermia may be neuroprotective in treating HIE, opening the door for further studies to examine alternative or adjuvant therapies to hypothermia.
The purpose of this study was to determine the potential neuroprotective effect of endothelin B (ET
) receptor agonist IRL-1620 treatment in a pediatric model of ischemic stroke.
A prospective, ...animal model study.
An experimental laboratory.
Three-month-old male Wistar Han rats.
The rats underwent permanent middle cerebral artery occlusion (MCAO). At 2, 4, and 6 h post MCAO, they were treated with saline, IRL-1620 (5 μg/kg, IV), and/or ET
antagonist BQ788 (1 mg/kg, IV).
The rats were evaluated over the course of 7 days for neurological and motor deficit, cerebral blood flow (CBF), and infarct volume. Young rats treated with IRL-1620 following MCAO improved significantly in neurological and motor assessments as compared to the vehicle-treated group, as measured by neurological score (
= 0.00188), grip test (
< 0.0001), and foot-fault error (
= 0.0075). CBF in the infarcted hemisphere decreased by 45-50% in all groups immediately following MCAO. After 7 days, CBF in the infarcted hemisphere of the IRL-1620 group increased significantly (
= 0.0007) when compared to the vehicle-treated group (+2.3 ± 23.3 vs. -45.4 ± 10.2%). Additionally, infarct volume was significantly reduced in IRL-1620-treated rats as compared to vehicle-treated rats (
= 0.0035, 41.4 ± 35.4 vs. 115.4 ± 40.9 mm
). Treatment with BQ788 blocked the effects of IRL-1620.
IRL-1620 significantly reduced neurological and motor deficit as well as infarct volume while increasing CBF in a pediatric rat model of cerebral ischemia. These results indicate that selective ET
receptor stimulation may provide a novel therapeutic strategy in the treatment of pediatric ischemic stroke as has been demonstrated in adult ischemic stroke.
Endothelin-B receptor agonist, IRL-1620, provides significant neuroprotection following cerebral ischemia in rats. Whether this neuroprotection is due to inhibition of apoptosis is unknown. ...IRL-1620-treated rats following permanent middle cerebral artery occlusion (MCAO) showed significant improvement in neurological and motor functions along with a decrease in infarct volume at 24 h (-81.3%) and day 7 (-73.0%) compared to vehicle group. Cerebral blood flow (CBF) significantly improved in IRL-1620-treated animals compared to vehicle by day 7 post MCAO. IRL-1620-treated rats showed an increase in phospho-Akt and decrease in Bad level 7 h post-occlusion compared to vehicle, while Akt and Bad expression was similar in cerebral hemispheres at 24 h post-MCAO. The phospho-Bad level was lower in vehicle- but not in IRL-1620-treated rats at 24 h. Anti-apoptotic Bcl-2 expression decreased, while pro-apoptotic Bax expression increased in vehicle-treated MCAO rats, these changes were attenuated (P < 0.01) by IRL-1620. Mitochondrial membrane-bound Bax intensity significantly decreased in IRL-1620 compared to vehicle-treated MCAO rats. IRL-1620 treatment reduced (P < 0.001) the number of TUNEL-positive cells compared to vehicle at 24 h and day 7 post MCAO. The results demonstrate that IRL-1620 is neuroprotective and attenuates neural damage following cerebral ischemia in rats by increasing CBF and reducing apoptosis.
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