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Cellular and Molecular Neurobiology Apr 2021Although therapeutic hypothermia (TH) provides neuroprotection, the cellular mechanism underlying the neuroprotective effect of TH has not yet been fully elucidated. In...
Although therapeutic hypothermia (TH) provides neuroprotection, the cellular mechanism underlying the neuroprotective effect of TH has not yet been fully elucidated. In the present study, we investigated the effect of TH on microglial activation to determine whether hypothermia attenuates neuronal damage via microglial activation. After lipopolysaccharide (LPS) stimulation, BV-2 microglia cells were cultured under normothermic (37 °C) or hypothermic (33.5 °C) conditions. Under hypothermic conditions, expression of pro-inflammatory cytokines and inducible nitric oxide synthase (iNOS) was suppressed. In addition, phagocytosis of latex beads was significantly suppressed in BV-2 cells under hypothermic conditions. Moreover, nuclear factor-κB signaling was inhibited under hypothermic conditions. Finally, neuronal damage was attenuated following LPS stimulation in neurons co-cultured with BV-2 cells under hypothermic conditions. In conclusion, hypothermia attenuates neuronal damage via inhibition of microglial activation, including microglial iNOS and pro-inflammatory cytokine expression and phagocytic activity. Investigating the mechanism of microglial activation regulation under hypothermic conditions could contribute to the development of novel neuroprotective therapies.
Topics: Animals; Cell Line; Cell Nucleus; Cytokines; Gene Expression Regulation; Hypothermia; Inflammation Mediators; Interleukin-1beta; Lipopolysaccharides; Mice, Inbred C57BL; Microglia; NF-kappa B; Neurons; Nitric Oxide Synthase Type II; Phagocytosis; Signal Transduction; Tumor Necrosis Factor-alpha; Mice
PubMed: 32382852
DOI: 10.1007/s10571-020-00860-z -
Psychopharmacology Jan 2024Clozapine N-oxide (CNO) has been developed as a ligand to selectively activate designer receptors exclusively activated by designer drugs (DREADDs). However, previous...
RATIONALE
Clozapine N-oxide (CNO) has been developed as a ligand to selectively activate designer receptors exclusively activated by designer drugs (DREADDs). However, previous studies have revealed that peripherally injected CNO is reverse-metabolized into clozapine, which, in addition to activating DREADDs, acts as an antagonist at various neurotransmitter receptors, suggesting potential off-target effects of CNO on animal physiology and behaviors. Recently, second-generation DREADD agonists compound 21 (C21) and JHU37160 (J60) have been developed, but their off-target effects are not fully understood.
OBJECTIVES
The present studies assessed the effect of novel DREADD ligands on reward-seeking behavior.
METHODS
We first tested the possible effect of acute i.p. injection of low-to-moderate (0.1, 0.3, 1, 3 mg/kg) of CNO, C21, and J60 on motivated reward-seeking behavior in wild-type mice. We then examined whether a high dose (10 mg/kg) of these drugs might be able to alter responding.
RESULTS
Low-to-moderate doses of all drugs and a high dose of CNO or C21 did not alter operant lick responding for a reward under a progressive ratio schedule of reinforcement, in which the number of operant lick responses to obtain a reward increases after each reward collection. However, high-dose J60 resulted in a total lack of responding that was later observed in an open field arena to be due to a sedative effect.
CONCLUSIONS
This study provides definitive evidence that commonly used doses of CNO, C21, and J60 have negligible off-target effects on motivated reward-seeking but urges caution when using high doses of J60 due to sedative effects.
Topics: Mice; Animals; Clozapine; Reward; Designer Drugs
PubMed: 37792024
DOI: 10.1007/s00213-023-06465-w -
Experimental Neurology Jul 2024Chronic hypoxia in utero causes intrauterine growth restriction (IUGR) of the fetus. IUGR infants are known to be at higher risk for neurodevelopmental disorders, but...
Chronic hypoxia in utero causes intrauterine growth restriction (IUGR) of the fetus. IUGR infants are known to be at higher risk for neurodevelopmental disorders, but the mechanism is unclear. In this study, we analyzed the structure of the cerebral cortex using IUGR model rats generated through a reduced uterine perfusion pressure operation. IUGR rats exhibited thinner cerebral white matter and enlarged lateral ventricles compared with control rats. Expression of neuron cell markers, Satb2, microtubule-associated protein (MAP)-2, α-tubulin, and nestin was reduced in IUGR rats, indicating that neurons were diminished at various developmental stages in IUGR rats, from neural stem cells to mature neurons. However, there was no increase in apoptosis in IUGR rats. Cells positive for Ki67, a marker of cell proliferation, were reduced in neurons and all glial cells of IUGR rats. In primary neuron cultures, axonal elongation was impaired under hypoxic culture conditions mimicking the intrauterine environment of IUGR infants. Thus, in IUGR rats, chronic hypoxia in utero suppresses the proliferation of neurons and glial cells as well as axonal elongation, resulting in cortical thinning and enlarged lateral ventricles. Thrombopoietin (TPO), a platelet growth factor, inhibited the decrease in neuron number and promoted axon elongation in primary neurons under hypoxic conditions. Intraperitoneal administration of TPO to IUGR rats resulted in increases in the number of NeuN-positive cells and the area coverage of Satb2. In conclusion, suppression of neuronal proliferation and axonal outgrowth in IUGR rats resulted in cortical thinning and enlargement of lateral ventricles. TPO administration might be a novel therapeutic strategy for treating brain dysmaturation in IUGR infants.
Topics: Animals; Fetal Growth Retardation; Rats; Neurons; Female; Cell Proliferation; Pregnancy; Thrombopoietin; Neuronal Outgrowth; Neuroprotective Agents; Rats, Sprague-Dawley; Cells, Cultured; Animals, Newborn; Cerebral Cortex
PubMed: 38636773
DOI: 10.1016/j.expneurol.2024.114781