International review of neurobiology最新文献

Many lines of research have suggested that the neuroactive pregnane steroids, including pregnenolone, progesterone, and allopregnanolone ([3α,5α]-3-hydroxypregnan-20-one, 3α,5α-THP), have therapeutic potential for treatment of alcohol use disorders (AUDs). In this chapter, we systematically address the preclinical and clinical evidence that supports this approach for AUD treatment, describe the underlying neurobiology of AUDs that are targeted by these treatments, and delineate how pregnane steroids may address various components of the disease. This review updates the theoretical framework for understanding how endogenous steroids that modulate the effects of alcohol, stress, excitatory/inhibitory and dopamine transmission, and the innate immune system appear to play a key role in the prevention and mitigation of AUDs. We further discuss newly discovered limitations of pregnane steroid therapies as well as the challenges that are inherent to development of endogenous compounds for therapeutics. We argue that overcoming these challenges presents the opportunity to help millions who suffer from AUDs across the world.

Cannabidiol (CBD) is one of over 200 cannabinoids present in the Cannabis plant. Unlike the plant's primary cannabinoid, delta-9-tetrahydrocannabinol (THC), CBD does not produce psychotomimetic effects nor induce dependence. Initially considered an inactive cannabinoid, interest in its pharmacological properties and therapeutic potential has grown exponentially over the last 20 years. Currently employed as a medication for certain epileptic syndromes, numerous pre-clinical and clinical studies support its potential use in various other disorders. In this chapter, we provide a brief historical overview of how this compound evolved from an "inactive substance" to a multifunctional clinical agent. Additionally, we discuss the current challenges in researching its potential therapeutic effects.

When identifying, preventing and treating alcohol use disorder, a correct estimation of alcohol intake is essential. An objective marker is preferred as self-reported alcohol intake suffers from bias, and the use of alcohol biomarkers is increasing globally. An easy-to-use blood biomarker to correctly assess alcohol consumption is an invaluable asset in alcohol treatment strategies, as well as in alcohol research studies. The specific, cumulative, biomarker phosphatidylethanol, mirroring the past two weeks of consumption, has shown superiority over traditional biomarkers and is an attractive choice of proxy for alcohol intake.

The aim of supportive management of motor neuron disease is to improve survival, promote good quality of life and patient independence and autonomy whilst preparing for future progression and the end of life. Multidisciplinary specialist care aims to address the multifaceted and interacting biopsychosocial problems associated with motor neuron disease that leads to proven benefits in both survival and quality of life. This chapter will explore principles, structure and details of treatment options, and make recommendations for practice and for future research.

Inflammation is a fundamental part of the body's natural defense mechanism, involving immune cells and inflammatory mediators to promote healing and protect against harm. In the event of a lesion or disease of the somatosensory nervous system, inflammation, however, triggers a cascade of changes in both the peripheral and central nervous systems, ultimately contributing to chronic neuropathic pain. Substantial evidence links neuroinflammation to various conditions associated with neuropathic pain. This chapter will explore the role of neuroinflammation in the initiation, maintenance, and resolution of peripheral and central neuropathic pain. Additionally, biomarkers of neuroinflammation in humans will be examined, emphasizing their relevance in different neuropathic pain disorders.

Affective neuropsychiatric disorders such as depression, anxiety and apathy are among the most frequent non-motor symptoms observed in people with Parkinson's disease (PD). These conditions often emerge during the prodromal phase of the disease and are generally considered to result from neurodegenerative processes in meso-corticolimbic structures, occurring in parallel to the loss of nigrostriatal dopaminergic neurons. Depression, anxiety, and apathy are often treated with conventional medications, including selective serotonin reuptake inhibitors, tricyclic antidepressants, and dopaminergic agonists. The ability of these pharmacological interventions to consistently counteract such neuropsychiatric symptoms in PD is still relatively limited and the development of reliable experimental models represents an important tool to identify more effective treatments. This chapter provides information on rodent models of PD utilized to study these affective neuropsychiatric symptoms. Neurotoxin-based and genetic models are discussed, together with the main behavioral tests utilized to identify depression- and anxiety-like behaviors, anhedonia, and apathy. The ability of various therapeutic approaches to counteract the symptoms observed in the various models is also reviewed.

Alcohol dependence (AD) significantly impacts public health, affecting 3.4% of people aged 18-64 and contributing to around 12% of overall mortality. Individuals with AD have a markedly reduced life expectancy, dying up to 28 years earlier than the general population. Current treatments for AD show limited efficacy, with many patients not responding to these interventions, highlighting the need for new therapeutic options with novel mechanisms of action. Sodium oxybate (SMO), the sodium salt of GHB, is one such candidate, pharmacologically similar to alcohol; it acts on several neurotransmitters including GABA, potentially mitigating withdrawal symptoms and craving for alcohol. SMO has been clinically used in Italy and Austria since the 1990s, approved for treating alcohol withdrawal syndrome (AWS) and for maintaining abstinence in AD patients. Several randomized clinical trials (RCTs) and meta-analyses showed evidence of SMO to be effective and safe in these indications. For AWS, SMO was more effective than placebo and as effective as benzodiazepines in reducing withdrawal symptoms. For maintaining abstinence, SMO significantly improved continuous abstinence duration and abstinence rate compared to placebo. Comprehensive clinical data indicate that SMO is well-tolerated, with main adverse effects being mild, such as dizziness and vertigo, and serious adverse events being rare. The effectiveness and safety of SMO, coupled with its approval in two EU countries affirm its potential as a treatment option for AD, particularly in severe cases. Further RCTs, especially with stratification by severity of dependence, are suggested to refine our understanding of its efficacy across different patient subgroups.

New approaches for the treatment of alcohol dependence (AD) may improve patient outcomes. Substitution maintenance therapy is one of the most effective treatment options for opioid and nicotine use disorders. So far, there has been little attention to substitution therapy for the treatment of AD. Here, we explain the mechanistic foundations of alcohol substitution maintenance therapy. Alcohol has many primary targets in the brain (and other organs) and the physical interaction of ethanol molecules with these specific ethanol-sensitive sites on a variety of ionotropic receptors (e.g. GABA-A, NMDA, and nicotinic acetylcholine (nACh) receptors) and ion channels provides the rationale for substitution. As such, a variety of compounds can interact with those ethanol-sensitive sites and can thus substitute for some of the effects of alcohol. For some of these compounds, alcohol discrimination studies have shown their substitution potential. Accordingly, potential substitution treatments include agonists acting at GABA receptors such as sodium oxybate, baclofen and benzodiazepines, NMDA receptor antagonists such as ketamine and memantine, or nAChRs agonists such as varenicline. All these compounds are already approved for other indications and we present clinical evidence for these drugs in the treatment of alcohol withdrawal syndrome (AWS) and in the long-term treatment of AD, and outline future steps for their acceptance as substitution treatment in AD. Finally, we discuss the substitution approach of managed alcohol programs for the most severely affected homeless populations. Results showed that sodium oxybate is probably the closest to a substitution therapy for AD and is already approved for the treatment of AWS and in the long-term treatment of AD in some countries. In conclusion, we argue that better AD treatment can be provided if substitution maintenance treatments for alcohol are implemented at a similar scale as for opioid and nicotine use disorder.

The health risks and harm associated with regular alcohol consumption are well documented. In a recent WHO statement published in The Lancet Public Health alcohol consumption has been estimated to contribute worldwide to 3 million deaths in 2016 while also being responsible for 5·1% of the global burden of disease and injury. The total elimination of alcohol consumption, which has been long imbedded in human culture and society, is not practical and prohibition policies have proved historically ineffective. However, valuable strategies to reduce alcohol harms are already available and improved alternative approaches are currently being developed. Here, we will review and discuss recent advances on two main types of approaches, that is nutritional interventions and functional alcohol alternatives.

Decades of research have implicated the gamma-aminobutyric acid (GABA)ergic system as one of the main mediators of the behavioral effects of alcohol. Of importance, the addiction-related effects of alcohol also have been shown to be mediated in part by GABAergic systems, raising the possibility that pharmacotherapies targeting GABAergic receptors may be promising candidates for the treatment of alcohol use disorder (AUD). Alcohol modulates the activity of GAB_AA and GA_BA_B receptors, and studies show that compounds targeting some of those receptors may decrease the addiction-related behavioral effects of alcohol. Specifically, drugs that share similar pharmacological properties with alcohol, such as positive allosteric modulators (PAMs) of GAB_AA and GA_BA_B receptors, have been proposed as substitution therapies for AUD. Available evidence also suggests that negative allosteric modulators (NAMs) of GABAergic receptors may be potential therapeutics for AUD, although this effect is selective for specific receptor subtypes. Therefore, this Chapter reviews the available evidence on the use of GABAergic compounds for the treatment of AUD. Several GAB_AA and GA_BA_B ligands show promising results, with a particularly positive therapeutic profile demonstrated for α5GAB_AA receptor NAMs, α4/6δGAB_AA receptor modulators (both positive and negative, including neurosteroids), and GA_BA_B receptor PAMs. As newer and better GABAergic compounds become available, future research should focus on understanding how these ligands can modulate different clinical symptoms of AUD, with potential new areas of research encompassing alcohol withdrawal syndrome and AUD-related insomnia.