Behavioral pharmacology of five novel synthetic cannabinoids.

Newly emerging synthetic cannabinoid compounds continue to be found in the designer drug market. They are often targeted as a 'legal high' alternative to traditional cannabinoids via 'darknet' markets and their increased potency and efficacy are becoming a growing concern internationally. The purpose of this study was to determine whether 4-CN-CUMYL-BUTINACA, 4F-MDMB-BINACA, 5F-AEB, 5F-CUMYL-P7AICA and EMB-FUBINACA exhibited similar behavioral effects as Δ9-tetrahydrocannabinol (Δ9-THC).

Glatiramer Acetate Reverses Motor Dysfunction and the Decrease in Tyrosine Hydroxylase Levels in a Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease and there are no effective treatments that either slow or reverse the degeneration of the dopamine (DA) pathway. Using a 4-week progressive MPTP (1-methyl-1,2,3,6-tetrahydropyridine) neurotoxin model of PD, which is characterized by neuroinflammation, loss of nigrostriatal DA, and motor dysfunction, as seen in patients with PD, we tested whether post-MPTP treatment with glatiramer acetate (GA), an immunomodulatory drug, could reverse these changes. GA restored the grip dysfunction and gait abnormalities that were evident in the MPTP treated group.

Remote ischemic conditioning for stroke: clinical data, challenges, and future directions.

Despite great improvement during the past several decades, the management of stroke is still far from satisfactory, which warrants alternative or adjunctive strategies. Remote ischemic conditioning (RIC), an easy-to-use and noninvasive therapy, can be performed in various clinical scenarios (e.g.

Cannabinoid-like effects of five novel carboxamide synthetic cannabinoids.

A new generation of novel cannabinoid compounds have been developed as marijuana substitutes to avoid drug control laws and cannabinoid blood tests. 5F-MDMB-PINACA (also known as 5F-ADB, 5F-ADB-PINACA), MDMB-CHIMICA, MDMB-FUBINACA, ADB-FUBINACA, and AMB-FUBINACA (also known as FUB-AMB, MMB-FUBINACA) were tested for in vivo cannabinoid-like effects to assess their abuse liability. Locomotor activity in mice was tested to screen for locomotor depressant effects and to identify behaviorally-active dose ranges and times of peak effect.

Gait Analyses in Mice: Effects of Age and Glutathione Deficiency.

Minor changes (~0.1 m/s) in human gait speed are predictive of various measures of decline and can be used to identify at-risk individuals prior to further decline. These associations are possible due to an abundance of human clinical research.

Tyrosine Hydroxylase Inhibition in Substantia Nigra Decreases Movement Frequency.

Reduced movement frequency or physical activity (bradykinesia) occurs with high prevalence in the elderly. However, loss of striatal tyrosine hydroxylase (TH) in aging humans, non-human primates, or rodents does not reach the ~ 80% loss threshold associated with bradykinesia onset in Parkinson's disease. Moderate striatal dopamine (DA) loss, either following TH inhibition or decreased TH expression, may not affect movement frequency.

Adverse Neuropsychiatric Events and Recreational Use of Efavirenz and Other HIV-1 Antiretroviral Drugs.

Efavirenz is a highly effective HIV-1 antiretroviral; however, it is also frequently associated with neuropsychiatric adverse events (NPAE) that include abnormal dreams, sleep disturbances, nervousness, anxiety, depression, and dizziness. The incidence of NPAEs upon initiation of treatment with efavirenz-containing medications is high, exceeding 50% in most studies. Although the NPAEs tend to decrease after the first month in many patients, they persist for long periods of time in others.

Plasma pentraxin 3 and glucose kinetics following acute high-intensity interval exercise versus continuous moderate-intensity exercise in healthy men.

Pentraxin 3 (PTX3) is mainly synthesized and released by neutrophils to help regulate innate immunity. While plasma PTX3 concentrations are associated with improved glucose metabolism and overall metabolic health, there is evidence that significant elevations in plasma glucose downregulate circulating levels of PTX3. To examine whether this relationship would be altered in response to exercise, this study investigated the kinetics of the plasma glucose and PTX3 responses following high-intensity interval exercise (HIIE) and continuous moderate-intensity exercise (CMIE).

Surgical management of giant intrapetrous internal carotid aneurysm presenting with coil exposure after endovascular treatment.

Giant intrapetrous internal carotid aneurysms (petrous ICA aneurysm) are rare. A giant petrous ICA aneurysm presenting with otorrhagia and coil exposure to the external auditory meatus (EAM) after endovascular treatment has never been documented before. The authors report here a case of successful surgical trapping with bypass intervention of a giant petrous ICA aneurysm presenting with coil exposure after endovascular treatment.

Tyrosine hydroxylase as a sentinel for central and peripheral tissue responses in Parkinson's progression: Evidence from clinical studies and neurotoxin models.

Parkinson's disease (PD) is a common neurodegenerative disease worldwide. While the typical motor symptoms of PD are well known, the lesser known non-motor symptoms can also greatly impact the patient's quality of life. These symptoms often appear before motor impairment, therefore identifying biomarkers that may predict PD risk or pathology has been a major and challenging endeavour.

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes-2.

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of Editorials, which are published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal Molecules [...

An exploratory investigation of brain-selective estrogen treatment in males using a mouse model of Alzheimer's disease.

Estrogens are neuroprotective, and studies suggest that they may mitigate the pathology and symptoms of Alzheimer's disease (AD) in female models. However, central estrogen effects have not been examined in males in the context of AD. The purpose of this follow-up study was to assess the benefits of a brain-selective 17β-estradiol estrogen prodrug, 10β,17β-hydroxyestra-1,4-dien-3-one (DHED), also in the male APPswe/PS1dE9 double-transgenic mouse model of the disease.

Aging-related limit of exercise efficacy on motor decline.

Identifying lifestyle strategies and allied neurobiological mechanisms that reduce aging-related motor impairment is imperative, given the accelerating number of retirees and increased life expectancy. A physically active lifestyle prior to old age can reduce risk of debilitating motor decline. However, if exercise is initiated after motor decline has begun in the lifespan, it is unknown if aging itself may impose a limit on exercise efficacy to decelerate further aging-related motor decline.

No Difference in Myosin Kinetics and Spatial Distribution of the Lever Arm in the Left and Right Ventricles of Human Hearts.

The systemic circulation offers larger resistance to the blood flow than the pulmonary system. Consequently, the left ventricle (LV) must pump blood with more force than the right ventricle (RV). The question arises whether the stronger pumping action of the LV is due to a more efficient action of left ventricular myosin, or whether it is due to the morphological differences between ventricles.

Genistein: mechanisms of action for a pleiotropic neuroprotective agent in stroke.

Genistein is a plant estrogen promoted as an alternative to post-menopausal hormone therapy because of a good safety profile and its promotion as a natural product. Several preclinical studies of cerebral ischemia and other models of brain injury support a beneficial role for genistein in protecting the brain from injury whether administered chronically or acutely. Like estrogen, genistein is a pleiotropic molecule that engages several different mechanisms to enhance brain health, including reduction of oxidative stress, promotion of growth factor signaling, and immune suppression.

Constitutive Ret signaling leads to long-lasting expression of amphetamine-induced place conditioning via elevation of mesolimbic dopamine.

Addictive drugs enhance dopamine release in the striatum, which can lead to compulsive drug-seeking after repeated exposure. Glial cell line-derived neurotrophic factor (GDNF) is an important regulator of midbrain dopamine neurons, and may play a mechanistic role in addiction-related behaviors. To elucidate the components of GDNF-signaling that contribute to addiction-related behaviors of place preference and its extinction, we utilized two genetically modified GDNF mouse models in an amphetamine-induced conditioned place preference (CPP) paradigm and evaluated how the behavioral findings correlate with dopamine signaling in the dorsal and ventral striatum.

Administration of 5-methoxyindole-2-carboxylic acid that potentially targets mitochondrial dihydrolipoamide dehydrogenase confers cerebral preconditioning against ischemic stroke injury.

The objective of this study was to investigate a possible role of mitochondrial dihydrolipoamide dehydrogenase (DLDH) as a chemical preconditioning target for neuroprotection against ischemic injury. We used 5-methoxyindole-2-carboxylic acid (MICA), a reportedly reversible DLDH inhibitor, as the preconditioning agent and administered MICA to rats mainly via dietary intake. Upon completion of 4 week's MICA treatment, rats underwent 1h transient ischemia and 24h reperfusion followed by tissue collection.

Pancreatic mitochondrial complex I exhibits aberrant hyperactivity in diabetes.

It is well established that NADH/NAD redox balance is heavily perturbed in diabetes, and the NADH/NAD redox imbalance is a major source of oxidative stress in diabetic tissues. In mitochondria, complex I is the only site for NADH oxidation and NAD regeneration and is also a major site for production of mitochondrial reactive oxygen species (ROS). Yet how complex I responds to the NADH/NAD redox imbalance and any potential consequences of such response in diabetic pancreas have not been investigated.

Discriminative stimulus and locomotor effects of para-substituted and benzofuran analogs of amphetamine.

Novel psychoactive substances have maintained a prominent role in the global drug culture, despite increased regulation by governing bodies. Novel compounds continue to become available on the market, often in "Ecstasy" or "Molly" formulations in lieu of MDMA, at a much faster rate than they can be properly characterized. The current study aimed to investigate the discriminative stimulus and locomotor effects of three putatively entactogenic compounds that have become increasingly prevalent on the drug market: 5-(2-aminopropyl)-benzofuran (5-APB), 6-(2-aminopropryl)-2,3-dihydrobenzofuran (6-APDB), and 4-fluoroamphetamine (4-FA).

Presence of Androgen Receptor Variant in Neuronal Lipid Rafts.

Fast, nongenomic androgen actions have been described in various cell types, including neurons. However, the receptor mediating this cell membrane-initiated rapid signaling remains unknown. This study found a putative androgen receptor splice variant in a dopaminergic N27 cell line and in several brain regions (substantia nigra pars compacta, entorhinal cortex, and hippocampus) from gonadally intact and gonadectomized (young and middle-aged) male rats.

Intermittent hypoxia training: Powerful, non-invasive cerebroprotection against ethanol withdrawal excitotoxicity.

Ethanol intoxication and withdrawal exact a devastating toll on the central nervous system. Abrupt ethanol withdrawal provokes massive release of the excitatory neurotransmitter glutamate, which over-activates its postsynaptic receptors, causing intense Ca loading, p38 mitogen activated protein kinase activation and oxidative stress, culminating in ATP depletion, mitochondrial injury, amyloid β deposition and neuronal death. Collectively, these mechanisms produce neurocognitive and sensorimotor dysfunction that discourages continued abstinence.

Bone-targeted cabazitaxel nanoparticles for metastatic prostate cancer skeletal lesions and pain.

Aim: The aim of this study was to develop a novel cabazitaxel bone targeted nanoparticle (NP) system for improved drug delivery to the bone microenvironment.

Materials & Methods: Nanoparticles were developed using poly(D,L-lactic-co-glycolic acid) and cabazitaxel as the core with amino-bisphosphonate surface conjugation. Optimization of nanoparticle physiochemical properties, in vitro evaluation in prostate cancer cell lines and in vivo testing in an intraosseous model of metastatic prostate cancer was performed.

Duration of isoflurane-based surgical anesthesia determines severity of brain injury and neurological deficits after a transient focal ischemia in young adult rats.

Tremendous efforts and funds invested in discovery of novel drug treatments for ischemic stroke have so far failed to deliver clinically efficacious therapies. The reasons for these failures are not fully understood. An indiscriminate use of isoflurane-based surgical anesthesia with or without nitrous oxide may act as an unconstrained, untraceable source of data variability, potentially causing false-positive or false-negative results.

Nanomaterial applications for neurological diseases and central nervous system injury.

The effectiveness of noninvasive treatment for neurological disease is generally limited by the poor entry of therapeutic agents into the central nervous system (CNS). Most CNS drugs cannot permeate into the brain parenchyma because of the blood-brain barrier thus, overcoming this problem has become one of the most significant challenges in the development of neurological therapeutics. Nanotechnology has emerged as an innovative alternative for treating neurological diseases.