The latest articles about Neuropharmacology
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This week, we would like to share the latest articles about Neuropharmacology.
Title: Ketamine; history and role in anesthetic pharmacology
Authors: Kazuyoshi Hirota，David G Lambert
- Development of ketamine in 1962 as a less hallucinogenic agent than phencyclidine.
- Adverse reactions: raised intracranial and blood pressures, psychiatric reaction.
- Benefits for invasive surgery: analgesia, antishock and anti-inflammatory effects.
- Other benefits: antitumor, antiasthmatic and antidepressive actions, neuroprotection.
Ketamine (Ket) was developed in 1962 as a less hallucinogenic and shorter acting agent than phencyclidine. It was given to humans for the first time in 1964. However, Ket produces several adverse reactions such as raised intracranial and blood pressures along with seizures, and patients still show low acceptance due to hallucinations. As new volatile and intravenous anesthetic agents with good emergence and favorable side effect profiles were developed, Ket use markedly decreased. In the 1990s, as the ultrashort-acting opioid remifentanil was developed, high dose opioid could be used to reduce surgical stress in highly invasive procedures. However, high dose opioids can produce hyperalgesia and acute tolerance. As Ket can exert anti-hyperalgesic actions, the clinical use of low dose Ket has been reconsidered. Other beneficial effects of Ket such as; analgesia, anti-shock in hemorrhagic and septic insults, anti-inflammatory effects, anti-tumor effects, brain and spinal cord neuroprotection, and bronchodilation, have all been reported. Moreover, this anesthetic agent at low dose has been recently recognized to possess anti-depressive actions. This diverse profile extends Ket far beyond anesthesia practice and the operating room.
Access this article: https://doi.org/10.1016/j.neuropharm.2022.109171
Title: Fingolimod attenuates gait deficits in mice subjected to experimental autoimmune encephalomyelitis
Authors: Gracious D. S. Kasheke，Scott P. Holman, George S. Pobertson.
Type: Short Communicate
Fingolimod, used to treat relapsing-remitting multiple sclerosis (RRMS), reduces motor deficits in mice with established experimental autoimmune encephalomyelitis (EAE). To better characterize the therapeutic effects of fingolimod, kinematic gait analysis was employed to precisely measure movements of a hindleg while EAE mice walked on a treadmill. Relative to the vehicle group, oral dosing with fingolimod, beginning after disease onset (1 mg/kg/day), increased hip heights and knee joint movements, and reduced spinal cord demyelination. These findings suggest that fingolimod preserves gait in RRMS patients by protecting motor circuits in the spinal cord.
Access this article: https://doi.org/10.1016/j.jneuroim.2022.577926
Title: Design and synthesis of chromone-based monoamine oxidase B inhibitors with improved drug-like properties
Authors: Joana Reis, Carlos Fernandes, Hoda Salem, Marta Maia, Claudia Tome, Sofia Benfeito, Jose Teixeira, Paulo J. Oliveira, Eugenio Uriarte, Francesco Ortuso， Stefano Alcaro，Donatella Bagetta， Fernando Cagide， Fernanda Borges.
Type: Research Article
- New chromone 3-phenylcarboxamide-based IMAO-B upsurge from lead optimization.
- Pioneering effective chromone 2-phenylcarboxamide based-IMAO-B were described.
- Chromones 38 and 41 stand out as the most potent/selective IMAO-B.
- Chromones 38 and 41 display favourable drug-like/cytotoxic/cytoprotective profiles.
The absence of disease modifying drugs in Parkinson's disease therapy urges for new chemical entities acting on relevant PD-associated biological targets. As a result, developing selective and reversible inhibitors targeting MAO-B is still a desirable line of therapeutic research. Within this framework, a small library of chromone derivatives was synthesized and screened towards human monoamine oxidases. Structural modifications on the chromone 3-phenylcarboxamide resulted in potent MAO-B inhibitors with an improved drug-like profile, and for the first time we obtained potent and selective chromone 2-phenylcarboxamides acting in the low nanomolar range. Compounds 5-hydroxy-4-oxo-N-phenyl-4H-chromene-3-carboxamide (38) (IC50 = 13.0 nM) and N-(4-chlorophenyl)-5-hydroxy-4-oxo-4H-chromene-3-carboxamide (41) (IC50 = 8.3 nM) stood out as reversible, potent, selective and non-cytotoxic MAO-B inhibitors bearing a favourable drug-like profile. Both compounds displayed cytoprotective effects towards iron(III) oxidative stressor.
Access this article: https://doi.org/10.1016/j.ejmech.2022.114507
Title: Eighteen-hour inhibitory effect of s-ketamine on potassium- and ischemia-induced spreading depolarizations in the gyrencephalic swine brain
Authors: Renan Sanchez-Porras, Modar Kentar, Roland Zerelles, Martina Geyer, Carlos Trenado, Jed A. Hartings, Johannes Woitzik, Jens P. Dreier, Edgar Santos.
Type: Research Article
- S-ketamine reduces SD frequency, expansion, speed, and amplitude during 18 h in a potassium induced SD swine model.
- S-ketamine reduces SD frequency and expansion during 18 h after experimental stroke in the swine brain.
- Administration of s-ketamine over 18 h did not show loss of its efficacy against SDs.
Spreading depolarizations (SDs) are characterized by near-complete breakdown of the transmembrane ion gradients, cytotoxic edema, and glutamate release. SDs are associated with poor neurological outcomes in cerebrovascular diseases and brain trauma. Ketamine, a N-methyl-D-aspartate receptor antagonist, has shown to inhibit SDs in animal models and in humans. However, little is known about its SD-inhibitory effect during long-term administration. Lissencephalic animal models have shown that ketamine loses its SD-blocking effect after some minutes to hours. Physio-anatomical differences between lissencephalic and the more evolved gyrencephalic animals may affect their SDs-blocking effect. Therefore, information from the last may have more translational potential. Therefore, the aim of this study was to investigate the 18 h-effect of s-ketamine as a basis for its possible long-term clinical use for neuroprotection. For this purpose, two gyrencephalic swine brain models were used. In one, SDs were elicited through topical application of KCl; in the other model, SDs were spontaneously induced after occlusion of the middle cerebral artery. S-ketamine was administered at therapeutic human doses, 2, 4 and 5 mg/ kg BW/h for up to 18 h. Our findings indicate that s-ketamine significantly reduces SD incidence and expansion without clear evidence of loss of its efficacy. Pharmacological susceptibility of SDs to s-ketamine in both the ischemic gyrencephalic brain and well-perfused brain was observed. SDs were most potently inhibited by s-ketamine doses that are above the clinically recommended (4 mg/kg BW/h and 5 mg/kg BW/h). Nonetheless, such doses are given by neurointensivists in individual cases. Our results give momentum to further investigate the feasibility of a multicenter, neuromonitoring-guided, proof-of-concept clinical trial.
Access this article: https://doi.org/10.1016/j.neuropharm.2022.109176
Title: A peptide inhibitor that rescues polyglutamine-induced synaptic defects and cell death through suppressing RNA and protein toxicities
Authors: Shaohong Isaac Peng, Lok I. Leong, Jacquelyne Ka-Li Sun, Zhefan Stephen Chen, Hei-Man Chow, Ho Yin Edwin Chan.
Type: Research Article
Polyglutamine (polyQ) diseases, including spinocerebellar ataxias and Huntington’s disease, are progressive neurodegenerative disorders caused by CAG triplet-repeat expansion in the coding regions of disease-associated genes. In this study, we found that neurotoxic small CAG (sCAG) RNA species, microscopic Ataxin-2 CAG RNA foci, and protein aggregates exist as independent entities in cells. Synaptic defects and neurite outgrowth abnormalities were observed in mutant Ataxin-2-expressing mouse primary cortical neurons. We examined the suppression effects of the CAG RNA-binding peptide beta-structured inhibitor for neurodegenerative diseases (BIND) in mutant Ataxin-2-expressing mouse primary cortical neurons and found that both impaired synaptic phenotypes and neurite outgrowth defects were rescued. We further demonstrated that BIND rescued cell death through inhibiting sCAG RNA production, Ataxin-2 CAG RNA foci formation, and mutant Ataxin-2 protein translation. Interestingly, when the expanded CAG repeats in the mutant Ataxin-2 transcript was interrupted with the alternative glutamine codon CAA, BIND’s inhibitory effect on mutant protein aggregation was lost. We previously demonstrated that BIND interacts physically and directly with expanded CAG RNA sequences. Our data provide evidence that the BIND peptide associates with transcribed mutant CAG RNA to inhibit the formation of toxic species, including sCAG RNA, RNA foci, and polyQ protein translation and aggregation.
Access this article: https://doi.org/10.1016/j.omtn.2022.06.004