Amantadine for Traumatic Brain Injury-Supporting Evidence and Mode of Action.

Traumatic brain injury (TBI) is an important global clinical issue, requiring not only prevention but also effective treatment. Following TBI, diverse parallel and intertwined pathological mechanisms affecting biochemical, neurochemical, and inflammatory pathways can have a severe impact on the patient's quality of life. The current review summarizes the evidence for the utility of amantadine in TBI in connection to its mechanism of action.

Amantadine Inhibits SARS-CoV-2 In Vitro.

Since the SARS-CoV-2 pandemic started in late 2019, the search for protective vaccines and for drug treatments has become mandatory to fight the global health emergency. Travel restrictions, social distancing, and face masks are suitable counter measures, but may not bring the pandemic under control because people will inadvertently or at a certain degree of restriction severity or duration become incompliant with the regulations. Even if vaccines are approved, the need for antiviral agents against SARS-CoV-2 will persist.

Amantadine: reappraisal of the timeless diamond-target updates and novel therapeutic potentials.

The aim of the current review was to provide a new, in-depth insight into possible pharmacological targets of amantadine to pave the way to extending its therapeutic use to further indications beyond Parkinson's disease symptoms and viral infections. Considering amantadine's affinities in vitro and the expected concentration at targets at therapeutic doses in humans, the following primary targets seem to be most plausible: aromatic amino acids decarboxylase, glial-cell derived neurotrophic factor, sigma-1 receptors, phosphodiesterases, and nicotinic receptors. Further three targets could play a role to a lesser extent: NMDA receptors, 5-HT3 receptors, and potassium channels.

Can Sodium Thiosulfate Act as a Reversal Agent for Calcium Hydroxylapatite Filler? Results of a Preclinical Study.

Introduction: Calcium hydroxylapatite microspheres suspended in a gel carrier of sodium carboxymethylcellulose (CaHA; Radiesse) has demonstrated safe and effective restoration of facial volume in clinical trials, as well as collagen biostimulation leading to skin quality improvement. The potential with CaHA, as with any filler, to produce overcorrection and subsequent complications has led to the search for a reversal agent. Sodium thiosulfate (STS) was proposed based on experience with it as a chelating agent to treat calciphylaxis.

The effect of the perfluorodecalin patch on particle emission and skin temperature during laser-induced tattoo removal.

Laser-based procedures for tattoo removals are popular due to high efficacy and a relatively moderate insult. However, it often requires multiple sessions to achieve a satisfactory effect. The perfluorodecalin (PFD) patch utilizes an optical clearing agent to speed up the removal process and may decrease skin insult and harmful particles emission during treatment.

Duration of a "Brown-Like" Phenotype of White Adipose Tissue Induced by the β3 Agonist CL-316,243.

"Browning" i. e. the transformation of white adipose tissue into brown-like adipose tissue could induce efficient burning of excess fat reserves via induction of non-shivering thermogenesis.

Rescue of Fmr1 phenotypes with mGluR inhibitors: MRZ-8456 versus AFQ-056.

Metabotropic glutamate receptor 5 (mGluR) is a drug target for central nervous system disorders such as fragile X syndrome that involve excessive glutamate-induced excitation. We tested the efficacy of a novel negative allosteric modulator of mGluR developed by Merz Pharmaceuticals, MRZ-8456, in comparison to MPEP and AFQ-056 (Novartis, a.k.

Browning of white adipose tissue induced by the ß3 agonist CL-316,243 after local and systemic treatment - PK-PD relationship.

Transformation of white adipose tissue (WAT) to a brown adipose tissue-like (BAT-like) phenotype has emerged as an attractive approach against obesity e.g. using g ß3 adrenergic receptor agonists.

Effects of the Positive Allosteric Modulator of Metabotropic Glutamate Receptor 5, VU-29, on Impairment of Novel Object Recognition Induced by Acute Ethanol and Ethanol Withdrawal in Rats.

Glutamate is essential for learning and memory processes, and acute and chronic exposures to ethanol (or protracted abstinence) alter glutamatergic transmission. In the current study, we investigated the effects of VU-29, positive allosteric modulator of metabotropic glutamate 5 (mGlu5) receptor, on the acute ethanol- and ethanol withdrawal-induced impairment of novel object recognition (NOR) task in rats. The influence of VU-29 (30 mg/kg) on memory retrieval was measured (a) at 4-h delay after acute ethanol administration, as well as (b) after acute withdrawal (24 and 48 h) of repeated (2.

ADX-47273, a mGlu5 receptor positive allosteric modulator, attenuates deficits in cognitive flexibility induced by withdrawal from 'binge-like' ethanol exposure in rats.

Repeated exposure to and withdrawal from ethanol induces deficits in spatial reversal learning. Data indicate that metabotropic glutamate 5 (mGlu5) receptors are implicated in synaptic plasticity and learning and memory. These receptors functionally interact with N-methyl-d-aspartate (NMDA) receptors, and activation of one type results in the activation of the other.

Further pharmacological characterization of eltoprazine: focus on its anxiolytic, anorexic, and adverse‑effect potential.

Eltoprazine, a drug that had previously been developed for aggression, has recently been investigated for L-DOPA-induced dyskinesia in animal models of Parkinson´s disease (PD) and in dyskinetic PD patients. Much less is known about effects of eltoprazine in other therapeutic indications. Indeed, the pharmacological profile of eltoprazine might suggest its effects on anxiety and food intake, but also adverse effect potential, which is the focus of the present study.

mGlu1 receptor as a drug target for treatment of substance use disorders: time to gather stones together?

Modulation of the mGlu1 receptor was repeatedly shown to inhibit various phenomena associated with exposure to abused drugs. Efficacy in preclinical models was observed with both positive and negative allosteric modulators (PAMs and NAMs, respectively) using essentially non-overlapping sets of experimental methods. Taken together, these data indicate that the mGlu1 receptor certainly plays a significant role in the plasticity triggered by the exposure to abused drugs and is involved in the maintenance of drug-seeking and drug-taking behaviors.

Optical isomers of phenibut inhibit [H(3)]-Gabapentin binding in vitro and show activity in animal models of chronic pain.

Background: We report that R- and S-phenibut (β-phenyl-γ-aminobutyric acid) - derivatives of GABA - bind with an affinity of c.a. 90μM to the gabapentin binding site in a competitive assay, a value comparable to that for previously claimed targets for this enantioermic molecule.

Effects of mGluR5 positive and negative allosteric modulators on brain damage evoked by hypoxia-ischemia in neonatal rats.

In the present study, we examined the effects of negative and positive allosteric modulators of metabotropic glutamate receptor 5 (mGluR5), fenobam and ADX47273, respectively, on brain damage induced by hypoxia-ischemia (H-I) in 7-day-old rats. The test drugs were administered intraperitoneally 10 min after H-I. Rectal body temperature was measured for 2.

Brain concentrations of mGluR5 negative allosteric modulator MTEP in relation to receptor occupancy--Comparison to MPEP.

Background: To verify relation between brain free levels, receptor occupancy in vivo and in vitro affinity at the target for mGluR5 negative allosteric modulator (NAM) MTEP.

Methods: We evaluated plasma and brain extra-cellular fluid (ECF) concentration of MTEP at behaviourally active dose (5mg/kg) using in vivo microdialysis. These values were compared it to the affinity in vitro (receptor binding and FLIPR) and to receptor occupancy in vivo.

Effects of sarizotan in animal models of ADHD: challenging pharmacokinetic-pharmacodynamic relationships.

Sarizotan 1-[(2R)-3,4-dihydro-2H-chromen-2-yl]-N-[[5-(4-fluorophenyl) pyridin-3-yl]methyl] methenamine, showed an in vivo pharmaco-EEG profile resembling that of methylphenidate which is used in attention deficit/hyperactivity disorder (ADHD). In turn, we tested sarizotan against impulsivity in juvenile rats measuring the choice for large delayed vs. a small immediate reward in a T-maze and obtained encouraging results starting at 0.

Effects of dopamine uptake inhibitor MRZ-9547 in animal models of Parkinson's disease.

MRZ-9547 (d-(2-(2-oxo-4(R)-phenylpyrrolidin-1-yl)-acetamide) is a drug acting at the dopamine transporter (DAT). In the present study, effects of MRZ-9547 alone and in combination with L-3,4-dihydroxyphenylalanine (L-DOPA) were investigated in rodent models predictive for efficacy in Parkinson's disease (PD) and L-DOPA-induced dyskinesia (LID). In rats pre-treated with haloperidol (0.

Memantine and cholinesterase inhibitors: complementary mechanisms in the treatment of Alzheimer's disease.

This review describes the preclinical mechanisms that may underlie the increased therapeutic benefit of combination therapy-with the N-methyl-D-aspartate receptor antagonist, memantine, and an acetylcholinesterase inhibitor (AChEI)-for the treatment of Alzheimer's disease (AD). Memantine, and the AChEIs target two different aspects of AD pathology. Both drug types have shown significant efficacy as monotherapies for the treatment of AD.

Using cholinergic M1 receptor positive allosteric modulators to improve memory via enhancement of brain cholinergic communication.

Benzylquinolone carboxylic acid (BQCA) is a recently described cholinergic muscarinic M(1) receptor positive allosteric modulator having potential as cognitive enhancer in dementia. The present study focused on the characterisation of BQCA's mode of action in relation to positive effects on memory and side-effects in an animal model. To get insight into this mode of action, in vitro receptor potency/left shift experiments in cells stably expressing the rat's M(1) receptor were performed.

Assessment of the effects of NS11394 and L-838417, α2/3 subunit-selective GABA(A) [corrected] receptor-positive allosteric modulators, in tests for pain, anxiety, memory and motor function.

The aim of the present paper was to study the effects of GABAA receptor-positive modulators (L-838417 and NS11394) showing a preference for α2/3 subunits of the GABAA receptor, in models of pain, anxiety, learning, memory and motor function. These compounds have been suggested to have a favourable therapeutic profile over nonselective compounds such as diazepam. In this study, we tested both compounds for their effects in rat models of formalin-induced pain, spinal nerve-ligation-induced mechanical allodynia, plus maze, open field, rotarod, balance beam walking, contextual fear conditioning and Morris water maze.

Effect of 5-HT5A antagonists in animal models of schizophrenia, anxiety and depression.

The few available data on the pharmacological effect of 5-HT5A receptors suggest that antagonists may have anxiolytic, antidepressant and antipsychotic activity. The aim of our study was to verify these suggestions in relevant animal models. Two 5-HT5A antagonist ligands, SB-699551-A (N-[2-(dimethylamino)ethyl]-N-[[4'-[[(2-phenylethyl)amino]methyl][1,1'-biphenyl]-4-yl]methyl]cyclopentanepropanamide dihydrochloride) (3-60 mg/kg, intraperitoneally) and A-843277 (N-(2,6-dimethoxybenzyl)-N'[4-(4-fluorophenyl)thiazol-2-yl]guanidine) (3-30 mg/kg, intraperitoneally), were examined in the open-field test, in a foot-shock-induced ultrasonic vocalization test, in the forced swim test (FST) and in the amphetamine-induced and phencyclidine-induced hyperlocomotion tests to examine their effect on general behavioural patterns, and their anxiolytic-like, antidepressant-like and antipsychotic-like properties, respectively.

Alzheimer's disease, β-amyloid, glutamate, NMDA receptors and memantine--searching for the connections.

β-amyloid (Aβ) is widely accepted to be one of the major pathomechanisms underlying Alzheimer's disease (AD), although there is presently lively debate regarding the relative roles of particular species/forms of this peptide. Most recent evidence indicates that soluble oligomers rather than plaques are the major cause of synaptic dysfunction and ultimately neurodegeneration. Soluble oligomeric Aβ has been shown to interact with several proteins, for example glutamatergic receptors of the NMDA type and proteins responsible for maintaining glutamate homeostasis such as uptake and release.

The role of group I mGlu receptors in the expression of ethanol-induced conditioned place preference and ethanol withdrawal seizures in rats.

In animal models, N-methyl-D-aspartate (NMDA) receptors antagonists inhibit physical dependence and the reinforcing effects of ethanol. The group I metabotropic glutamate (mGlu) receptors antagonists (mGlu1 and mGlu5) attenuate excitatory effect of glutamate by functional modulation of the glutamate/NMDA receptors. The objective of the present study was to evaluate the effects of a selective mGlu5 receptors antagonist--MTEP, and mGlu1 receptors antagonist--EMQMCM, on two processes relevant to alcohol addiction: the expression of ethanol-induced conditioned place preference (CPP) paradigm, and ethanol withdrawal audiogenic seizures in rats.

Behavioural and cellular effects of exogenous amyloid-β peptides in rodents.

A better understanding of Alzheimer's disease (AD) and the development of disease modifying therapies are some of the biggest challenges of the 21st century. One of the core features of AD are amyloid plaques composed of amyloid-beta (Aβ) peptides. The first hypothesis proposed that cognitive deficits are linked to plaque-development and transgenic mice have been generated to study this link, thereby providing a good model to develop new therapeutic approaches.

Evaluation of brain pharmacokinetics of (+)MK-801 in relation to behaviour.

The non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist (+)MK-801 is widely used in animal research (over 3000 publications), however its extracellular brain concentration has never been reported. Here, we show using in vivo microdialysis that systemic injection of (+)MK-801 at doses of 0.05, 0.