The Role of Histone Deacetylase 3 Complex in Nuclear Hormone Receptor Action

Nuclear hormone receptors (NRs) regulate transcription of the target genes in a ligand-dependent manner in either a positive or negative direction, depending on the case. Deacetylation of histone tails is associated with transcriptional repression. A nuclear receptor corepressor (N-CoR) and a silencing mediator for retinoid and thyroid hormone receptors (SMRT) are the main corepressors responsible for gene suppression mediated by NRs. Among numerous histone deacetylases (HDACs), HDAC3 is the core component of the N-CoR/SMRT complex, and plays a central role in NR-dependent repression. Here, the roles of HDAC3 in ligand-independent repression, gene repression by orphan NRs, NRs antagonist action, ligand-induced repression, and the activation of a transcriptional coactivator are reviewed. In addition, some perspectives regarding the non-canonical mechanisms of HDAC3 action are discussed.

The therapeutic benefits of natural cannabinoids in delaying the pathophysiology of Alzheimer's disease

Objectives: To analyze and evaluate the current conjuncture inherent to the therapeutic use of natural cannabinoids in delay and protection against the pathophysiological actions caused by Alzheimer's disease. Methods: Overview of systematic reviews. The search and selection of the studies were predominantly in the databases of the Medical Literature Analysis and Retrieval System Online (Medline), National Library of Medicine (Pubmed) and Scientific Electronic Library Online (SciELO) in the period between March and August 2020. Key findings: Current results showed promising therapeutic effects of natural cannabinoids in the treatment of Alzheimer's disease, such as reduction of motor and cognitive symptoms, and protective neuroprotective action. These results can be explained, in part, by the anti-inflammatory, antioxidant, antagonist action of CB1 receptors, as well as by the activation of PPAR-gamma receptors produced by these substances. Conclusions: The systematic research presented in this overview converges in the sense that the therapeutic applications provided by natural cannabinoids and their analogues may play a unique role in the modulation of molecular targets involved in central nervous system dysfunctions caused by Alzheimer's disease, thus enabling the development of innovative drugs, safer and more effective in the treatment of patients not responsive to conventional clinical practice, with significant improvement in quality of life.

Flumazenil therapy for a gabapentin-induced coma: a case report

Background Spasticity and neuropathic pain are common in patients after spinal cord injury and negatively affect patients’ quality of life. Gabapentin and baclofen are frequently used to treat these conditions. We present a flumazenil-reversed gabapentin-induced coma case, which, to our knowledge, is the second one described in scientific literature. Case presentation A 70-year-old Caucasian man was admitted to our neurorehabilitation ward following a fall with cervical trauma that resulted in immediate tetraplegia. During his stay, he suffered from lower limb pain, both neuropathic and due to severe spasticity. Gradual baclofen and gabapentin administration was prescribed, with reduction in both pain and spasticity. One morning, the patient was found unresponsive, with a Glasgow Coma Score of 3. Head computerized tomography, electrocardiogram, electroencephalogram, vital signs, blood tests, breathing, and blood oxygenation were normal. Renal and liver failure were ruled out. Intravenous 0.25 mg of flumazenil (Anexate) was administered, resulting in complete neurocognitive recovery with a Glasgow Coma Score of 15. Discussion and conclusions This case report highlights the importance of the individual response to certain pharmacological agents and suggests that further studies need to be conducted both on flumazenil and gabapentin pharmacodynamics to better understand their molecular–receptor activity, and on possible multiple flumazenil mechanisms of action, beyond its classical strict benzodiazepine antagonist action.

That was then, this is now: the development of our knowledge and understanding of P2 receptor subtypes

P2 receptors are present in virtually all tissues and cell types in the human body, and they mediate the physiological and pharmacological actions of extracellular purine and pyrimidine nucleotides. They were first characterised and named by Geoff Burnstock in 1978, then subdivided into P2X and P2Y purinoceptors in 1985 on the basis of pharmacological criteria in functional studies on native receptors. Molecular cloning of receptors in the 1990s revealed P2X receptors to comprise seven different subunits that interact to produce functional homo- and heterotrimeric ligand-gated cation channels. A family of eight P2Y G protein–coupled receptors were also cloned, which can form homo- and heterodimers. Deep insight into the molecular mechanisms of agonist and antagonist action has been provided by more recent determination of the tertiary and quaternary structures of several P2X and P2Y receptor subtypes. Agonists and antagonists that are highly selective for individual subtypes are now available and some are in clinical use. This has all come about because of the intelligence, insight and drive of the force of nature that was Geoff Burnstock.

Binding and activation of serotonergic G-protein coupled receptors by the multimodal antidepressant vortioxetine

G-protein coupled receptors are important pharmacological targets. Despite substantial progress, important questions still remain concerning the details of activation: how can a ligand act as an agonist in one receptor, but as an antagonist in a homologous receptor, and how can agonists activate a receptor despite lacking polar functional groups able to interact with helix 5? Studying vortioxetine, an important multimodal antidepressant drug, may elucidate both questions. Herein, we present a thorough in silico analysis of vortioxetine binding to 5-HT1A, 5-HT1B, and 5-HT7 receptors and compare to available experimental data. We are able to rationalize the differential mode of action of vortioxetine at different receptors, but also, in the case of the 5-HT1A receptor, we observe the initial steps of activation suggesting that interaction with helix 5 does not necessarily require a hydrogen bond as previously suggested. The results extend our current understanding of agonist and antagonist action at GPCRs.

Magnesium and Pain

In terms of antinociceptive action, the main mode of action of magnesium involves its antagonist action at the N-methyl-d-aspartate (NMDA) receptor, which prevents central sensitization and attenuates preexisting pain hypersensitivity. Given the pivotal function of NMDA receptors in pain transduction, magnesium has been investigated in a variety of pain conditions. The oral and parenteral administration of magnesium via the intravenous, intrathecal, or epidural route may alleviate pain and perioperative anesthetic and analgesic requirements. These beneficial effects of magnesium therapy have also been reported in patients with neuropathic pain, such as malignancy-related neurologic symptoms, diabetic neuropathy, postherpetic neuralgia, and chemotherapy-induced peripheral neuropathy. In addition, magnesium treatment is reportedly able to alleviate fibromyalgia, dysmenorrhea, headaches, and acute migraine attacks. Although magnesium plays an evolving role in pain management, better understanding of the mechanism underlying its antinociceptive action and additional clinical studies is required to clarify its role as an adjuvant analgesic.

Beta-Blockers and Cancer: Where Are We?

Cancer is one of the leading causes of death worldwide. After diagnosis, cancer treatment may involve radiotherapy, chemotherapy, and surgery. Several of the approaches used to treat cancer also attack normal cells and, thus, there is the need for more effective treatments that decrease the toxicity to normal cells and increase the success rates of treatment. The use of beta-blockers in cancer has been studied for their antagonist action on the adrenergic system through inhibition of beta-adrenergic receptors. Besides regulating processes such as blood pressure, heart rate, and airway strength or reactivity, beta-blockers block mechanisms that trigger tumorigenesis, angiogenesis, and tumor metastasis. This study presents a literature review of the available studies addressing cancer treatments and beta-blockers. Overall, data suggest that propranolol may be used as a complement for the treatment of several types of cancer due to its ability to improve cancer outcomes by decreasing cancer cell proliferation rates. Nonetheless, additional in vitro studies should be performed to fully understand the protective role of BBs in cancer patients.

T215. THE ANTIPSYCHOTIC ACTION OF HALOPERIDOL IN PSYCHOTIC-LIKE RATS REQUIRES PRESYNAPTIC VESICULAR ACCUMULATION

Background The therapeutic effects of antipsychotic drugs (APDs) are mainly attributed to their post synaptic inhibitory functions on the dopamine D2 receptor, which however, cannot explain the delayed onset of full therapeutic efficacy. It was previously shown that APDs accumulate in presynaptic vesicles during chronic treatment and are released like neurotransmitters in an activity-dependent manner triggering an auto-inhibitory feedback mechanism. Although closely mirroring therapeutic action onset, the functional consequence of the APD accumulation remained unclear. Here we show that the accumulation of the APD haloperidol (HAL) is required for full therapeutic action in psychotic-like rats. Methods We designed a haloperidol (HAL) analogue compound (HAL-F), which lacks the accumulation property of HAL, but retains its antagonist action at dopamine D2 receptors. Results By perfusing lysotracker fluorophore-stained cultured hippocampal neurons, we confirmed the accumulation of HAL and the non-accumulation of HAL-F. In an AMPH-hypersensitization psychosis-like model in rats, we found that subchronic i.c.v. delivered HAL, but not HAL-F attenuates psychotic-like behavior in rats in an amphetamine-induced hyperlocomotion test and the a pre-puls inhibition of an acustic startle response. Discussion These findings suggest the presynaptic accumulation of HAL as an essential prerequisite for its full antipsychotic action and may better explain the time course of APD action. Targeting accumulation properties of APDs may, thus, become a new strategy to improve APD action.