scholarly journals Translating the immediate effects of S-Ketamine using hippocampal subfield analysis in healthy subjects-results of a randomized controlled trial

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Anna Höflich ◽  
Christoph Kraus ◽  
Ruth M. Pfeiffer ◽  
Rene Seiger ◽  
Dan Rujescu ◽  
...  
Keyword(s):  
Animal Models ◽  
Controlled Trial ◽  
Double Blind ◽  
Ca1 Region ◽  
Hippocampal Ca1 Region ◽  
Hippocampal Ca1 ◽  
Magnetic Resonance Imaging Mri ◽  
The Right ◽  
Mri Study ◽  
Post Hoc

AbstractAntidepressant doses of ketamine rapidly facilitate synaptic plasticity and modify neuronal function within prefrontal and hippocampal circuits. However, most studies have demonstrated these effects in animal models and translational studies in humans are scarce. A recent animal study showed that ketamine restored dendritic spines in the hippocampal CA1 region within 1 h of administration. To translate these results to humans, this randomized, double-blind, placebo-controlled, crossover magnetic resonance imaging (MRI) study assessed ketamine’s rapid neuroplastic effects on hippocampal subfield measurements in healthy volunteers. S-Ketamine vs. placebo data were analyzed, and data were also grouped by brain-derived neurotrophic factor (BDNF) genotype. Linear mixed models showed that overall hippocampal subfield volumes were significantly larger (p = 0.009) post ketamine than post placebo (LS means difference=0.008, standard error=0.003). Post-hoc tests did not attribute effects to specific subfields (all p > 0.05). Trend-wise volumetric increases were observed within the left hippocampal CA1 region (p = 0.076), and trend-wise volumetric reductions were obtained in the right hippocampal—amygdaloid transition region (HATA) (p = 0.067). Neither genotype nor a genotype–drug interaction significantly affected the results (all p > 0.7). The study provides evidence that ketamine has short-term effects on hippocampal subfield volumes in humans. The results translate previous findings from animal models of depression showing that ketamine has pro-neuroplastic effects on hippocampal structures and underscore the importance of the hippocampus as a key region in ketamine’s mechanism of action.

scholarly journals Intraarterial anti-leptin therapy via ICA protects ipsilateral CA1 neurons subjected to ischemia and reperfusion

PLoS ONE ◽  
2022 ◽  
Vol 17 (1) ◽  
pp. e0261644
Author(s):  
Amit Benbenishty ◽  
Jacob Schneiderman
Keyword(s):  
Carotid Artery ◽  
Common Carotid Artery ◽  
Right Hemisphere ◽  
Pyramidal Cells ◽  
Ca1 Neurons ◽  
Ca1 Region ◽  
Hippocampal Ca1 Region ◽  
Hippocampal Ca1 ◽  
The Right ◽  
Apoptosis And Necrosis

Background Brain reperfusion following an ischemic event is essential for tissue viability, however, it also involves processes that promote neuronal cell death. We have recently shown that local expression of the hormone leptin in cardiovascular organs drives deleterious remodeling. As cerebral ischemia-reperfusion (IR) lesions derive expression of both the leptin hormone and its receptor, we hypothesized that blocking leptin activity in the injured brain area will reduce the deleterious effects of IR injury. Methods C57BL6 male mice underwent bilateral common carotid artery and external carotid artery ligation. The right hemisphere was reperfused after 12 minutes, followed by intraarterial injection of either a low-dose leptin antagonist or saline solution via the ipsilateral ICA. The left common carotid artery remained ligated. Fifteen IR/leptin antagonist-injected and fourteen IR/saline-injected mice completed the experiment. Five days after surgery brains were collected and samples of the hippocampal CA1 region were analyzed for cell viability (H&E) and apoptosis (TUNEL and caspase3), for neuroinflammation (Iba1), and for signaling pathways of pSTAT3 and pSmad2. Results The right hemisphere hippocampal CA1 region subjected to IR and saline injection exhibited increased apoptosis and necrosis of pyramidal cells. Also, increased density of activated microglia/macrophages was evident around the CA1 region. Comparatively, leptin antagonist treatment at reperfusion reduced apoptosis and necrosis of pyramidal cells, as indicated by increased number of viable cells (p < 0.01), and reduced TUNEL (p < 0.001) and caspase3-positive cells (p<0.05). Furthermore, this treatment reduced the density of activated microglia/macrophages (p < 0.001) in the CA1 region. Signaling pathway analysis revealed that while pSTAT3 and pSmad2-positive cells were found surrounding the stratum pyramidal in saline-treated animals, pSTAT3 signal was undetected and pSmad2 was greatly reduced in this territory following leptin antagonist treatment (p < 0.01). Conclusions Inhibition of leptin activity in hemispheric IR injury preserved the viability of ipsilateral hippocampal CA1 neurons, likely by preventing apoptosis and local inflammation. These results indicate that intraarterial anti-leptin therapy may have clinical potential in reducing hemispheric brain IR injury.

scholarly journals Validation of the pediatric refractory septic shock definition: post hoc analysis of a controlled trial

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Luc Morin ◽  
Karthik Narayanan Ramaswamy ◽  
Muralidharan Jayashree ◽  
Arun Bansal ◽  
Karthi Nallasamy ◽  
...  
Keyword(s):  
Septic Shock ◽  
Intensive Care ◽  
Neonatal Intensive Care ◽  
Controlled Trial ◽  
Receiver Operating Curve ◽  
Double Blind ◽  
Post Hoc Analysis ◽  
Prognostic Accuracy ◽  
Refractory Septic Shock ◽  
Post Hoc

Abstract Background The European Society of Pediatric and Neonatal Intensive Care (ESPNIC) developed and validated a definition of pediatric refractory septic shock (RSS), based on two septic shock scores (SSS). Both bedside SSS (bSSS) and computed SSS (cSSS) were found to be strongly associated with mortality. We aimed at assessing the accuracy of the RSS definition on a prospective cohort from India. Methods Post hoc analysis of a cohort issued from a double-blind randomized trial that compared first-line vasoactive drugs in children with septic shock. Sequential bSSS and cSSS from 60 children (single-center study, 53% mortality) were analyzed. The prognostic value of the ESPNIC RSS definition was tested for 28-day all-cause mortality. Results In this septic shock cohort, RSS was diagnosed in 35 patients (58.3%) during the first 24 h. Death occurred in 30 RSS patients (85.7% mortality) and in 2 non-RSS patients (8% mortality), OR = 60.9 [95% CI: 10.5–676.2], p < 0.001 with a median delay from sepsis onset of 3 days [1.0–6.7]. Among patients diagnosed with RSS, the mortality was not significantly different according to vasopressors randomization. Diagnosis of RSS with bSSS and cSSS had a high discrimination for death with an area under the receiver operating curve of 0.916 [95% CI: 0.843–0.990] and 0.925 [95% CI: 0.845–1.000], respectively. High prognostic accuracy of the bSSS was found in the first hours following intensive care admission. The best interval of prognostication occurs after the 12th hour following treatment initiation (AUC 0.973 [95% CI: 0.925–1.000]). Conclusions The ESPNIC refractory septic shock definition accurately identifies, within the first 6 h of septic shock management, children with lethal outcome.

scholarly journals Early and sustained symptom improvement with umeclidinium/vilanterol versus monotherapy in COPD: a post hoc analysis of the EMAX randomised controlled trial

2020 ◽  
Vol 14 ◽  
pp. 175346662092694
Author(s):  
Edward M Kerwin ◽  
Isabelle H Boucot ◽  
Claus F Vogelmeier ◽  
Francois Maltais ◽  
Ian P Naya ◽  
...  
Keyword(s):  
Rescue Medication ◽  
Controlled Trial ◽  
Medication Use ◽  
Symptom Improvement ◽  
Chronic Obstructive ◽  
Electronic Diary ◽  
Double Blind ◽  
Clinical Trial Registration ◽  
Bronchodilator Therapy ◽  
Post Hoc

Background: In chronic obstructive pulmonary disease (COPD), both the time needed for patients to gain symptom improvement with long-acting bronchodilator therapy and whether an early response is predictive of a sustained response is unknown. This study aimed to investigate how quickly meaningful symptom responses are seen in patients with COPD with bronchodilator therapy and whether these responses are sustained. Methods: Early MAXimisation of bronchodilation for improving COPD stability (EMAX) was a 24-week, double-blind, double-dummy, parallel-group trial that randomised patients to umeclidinium/vilanterol (UMEC/VI), umeclidinium or salmeterol. Daily Evaluating Respiratory Symptoms in COPD (E-RS:COPD) score and rescue salbutamol use were captured via an electronic diary and analysed initially in 4-weekly periods. Post hoc analyses assessed change from baseline in daily E-RS:COPD score and rescue medication use weekly (Weeks 1–8), and association between E-RS:COPD responder status at Weeks 1–4 and later time points. Results: In the intent-to-treat population ( n = 2425), reductions from baseline in E-RS:COPD scores and rescue medication use were apparent from Day 2 with all treatments. Treatment differences for UMEC/VI versus either monotherapy plateaued by Week 4–8 and were sustained at Weeks 21–24; improvements were consistently greater with UMEC/VI. For all treatments, most patients (60–85%) retained their Weeks 1–4 E-RS:COPD responder/non-responder status at Weeks 21−24. Among patients receiving UMEC/VI who were E-RS:COPD responders at Weeks 1–4, 70% were responders at Weeks 21–24. Conclusion: Patients with symptomatic COPD had greater potential for early symptom improvements with UMEC/VI versus either monotherapy. This benefit was generally maintained for 24 weeks. Early monitoring of treatment response can provide clinicians with an early indication of a patient’s likely longer-term response to prescribed bronchodilator treatment and will facilitate appropriate early adjustments in care. Clinical Trial Registration: NCT03034915, 2016-002513-22 (EudraCT Number). The reviews of this paper are available via the supplemental material section.

Ultrastructure of stratum lacunosum moleculare interneurons of hippocampal CA1 region

Synapse ◽  
1988 ◽  
Vol 2 (4) ◽  
pp. 382-394 ◽  
Author(s):  
Dennis D. Kunkel ◽  
Jean-Claude Lacaille ◽  
Philip A. Schwartzkroin
Keyword(s):  
Ca1 Region ◽  
Hippocampal Ca1 Region ◽  
Hippocampal Ca1 ◽  
Stratum Lacunosum Moleculare

Chronic Effects of Pyridoxine in the Gerbil Hippocampal CA1 Region after Transient Forebrain Ischemia

2012 ◽  
Vol 37 (5) ◽  
pp. 1011-1018 ◽  
Author(s):  
Dae Young Yoo ◽  
Woosuk Kim ◽  
Sung Min Nam ◽  
Jin Young Chung ◽  
Jung Hoon Choi ◽  
...  
Keyword(s):  
Forebrain Ischemia ◽  
Transient Forebrain Ischemia ◽  
Ca1 Region ◽  
Hippocampal Ca1 Region ◽  
Chronic Effects ◽  
Hippocampal Ca1

Noradrenergic Regulation of Synaptic Plasticity in the Hippocampal CA1 Region

1997 ◽  
Vol 77 (6) ◽  
pp. 3013-3020 ◽  
Author(s):  
Hiroshi Katsuki ◽  
Yukitoshi Izumi ◽  
Charles F. Zorumski
Keyword(s):  
Synaptic Plasticity ◽  
Receptor Antagonist ◽  
Hippocampal Slices ◽  
Stimulus Frequency ◽  
Long Term Potentiation ◽  
Receptor Activation ◽  
Ca1 Region ◽  
Hippocampal Ca1 Region ◽  
Hippocampal Ca1

Katsuki, Hiroshi, Yukitoshi Izumi, and Charles F. Zorumski. Noradrenergic regulation of synaptic plasticity in the hippocampal CA1 region. J. Neurophysiol. 77: 3013–3020, 1997. The effects of norepinephrine (NE) and related agents on long-lasting changes in synaptic efficacy induced by several patterns of afferent stimuli were investigated in the CA1 region of rat hippocampal slices. NE (10 μM) showed little effect on the induction of long-term potentiation (LTP) triggered by theta-burst-patterned stimulation, whereas it inhibited the induction of long-term depression (LTD) triggered by 900 pulses of 1-Hz stimulation. In nontreated slices, 900 pulses of stimuli induced LTD when applied at lower frequencies (1–3 Hz), and induced LTP when applied at a higher frequency (30 Hz). NE (10 μM) caused a shift of the frequency-response relationship in the direction preferring potentiation. The effect of NE was most prominent at a stimulus frequency of 10 Hz, which induced no changes in control slices but clearly induced LTP in the presence of NE. The facilitating effect of NE on the induction of LTP by 10-Hz stimulation was blocked by theβ-adrenergic receptor antagonist timolol (50 μM), but not by the α receptor antagonist phentolamine (50 μM), and was mimicked by the β-agonist isoproterenol (0.3 μM), but not by the α1 agonist phenylephrine (10 μM). The induction of LTD by 1-Hz stimulation was prevented by isoproterenol but not by phenylephrine, indicating that the activation of β-receptors is responsible for these effects of NE. NE (10 μM) also prevented the reversal of LTP (depotentiation) by 900 pulses of 1-Hz stimulation delivered 30 min after LTP induction. In contrast to effects on naive (nonpotentiated) synapses, the effect of NE on previously potentiated synapses was only partially mimicked by isoproterenol, but fully mimicked by coapplication of phenylephrine and isoproterenol. In addition, the effect of NE was attenuated either by phentolamine or by timolol, indicating that activation of both α1 and β-receptors is required. These results show that NE plays a modulatory role in the induction of hippocampal synaptic plasticity. Althoughβ-receptor activation is essential, α1 receptor activation is also necessary in determining effects on previously potentiated synapses.

Sign in / Sign up

Export Citation Format

Share Document