Акампросат, механизм действия

Throughout the years, however, the molecular target of acamprosate has remained elusive. Because of structural similarities, initial hypotheses centered on the possibility that acamprosate may act as a GABA-mimic or otherwise modulate GABA-ergic transmission. There is, however, little in the in vivo profile of acamprosate to suggest similarities with drugs known to enhance GABA-ergic transmission. In fact, a lack of sedative–ataxic or addictive properties is among the clinical advantages of acamprosate. Once it became clear that acamprosate’s mechanism of action is likely to involve modulation of glutamatergic function, several potential mechanisms were explored. For instance, acamprosate was shown to possess some partial agonist activity on the NMDA receptor complex via actions at its polyamine site. This would potentially allow it to act as a functional antagonist during hyperglutamatergic states. However, experiments failed to demonstrate this kind of functional activity. More recently, focus shifted to potential activity of acamprosate at metabotropic glutamate receptors (mGluRs). This was prompted, for example, by observations that acamprosate blocked neurotoxicity induced by trans-ACPD, an mGluR agonist with affinity for mGluR1 and mGluR5 receptors (Kiefer and Mann, 2010).

Over the years, the notion has become widely accepted that, although we may not know its exact mechanism of action, acamprosate is ‘a functional glutamate antagonist’. The paper by Spanagel et al (2005) in this issue fundamentally challenges this notion. The paper presents multiple lines of evidence that the reason it has been difficult to pin down the molecular site of acamprosate action may simply be because it does not exist. Instead, the authors propose that the activity attributed to acamprosate has all along reflected actions of the Ca++ it carries. The authors first thoroughly excluded agonist as well as antagonist activity of acamprosate at the glycine or glutamate sites of the NMDA receptor, respectively, as well as at the mGluR5 receptor. They then went on to demonstrate in vivo that, in contrast to the Ca++ salt, the sodium salt of acamprosate did not suppress relapse-like drinking. Conversely, the delivery of comparable amounts of Ca++ using a different carrier, gluconate, replicated suppression of relapse-like drinking. These animal findings are supported by secondary analyses of clinical trial data, which indicate that in acamprosate-treated patients positive outcomes are strongly correlated with plasma Ca++ levels. No such correlation exists in placebo-treated patients.

Acamprosate: An Alcoholism Treatment That May Not Be What We Thought

Перспективные методы лечения депрессий

Long-term stress harms cells in the brain and body. Stressful experiences are believed to be closely associated with the development of psychological alterations and, thus, neuropsychiatric disorders.
In conditions of chronic stress exposure, nerve cells in the hippocampus begin to atrophy. (The hippocampus is a part of the brain involved with emotions, learning, and memory formation.)
The new depression theories “should not be viewed as separate entities because they are highly interconnected,” researchers write.
“Integrating them provides for a more expansive understanding of the pathophysiology of depression and biomarkers that are involved.”
Such biomarkers are molecules in the body that can be indicators of depression. The authors identify more than a dozen potential biomarkers depression, including monoamine regulators; proinflammatory cytokines and other inflammatory mediators; mediators of glutaminergic activity and GABAergic activity; and regulators of neurogenesis.
A bevy of new depression treatments are currently offered or on the horizon include corticotropin-releasing hormone antagonists; dexamethasone; partial adrenalectomy; long-term cognitive behavioral therapy; ketamine and other NMDA antagonists. Other treatments include benzodiazepines; anesthetics; deep brain stimulation; transcranial magnetic stimulation; exogenous brain-derived neurotrophic factor; selective serotonin reuptake inhibitors; tricyclic antidepressants; atypical antidepressants; reduction in inflammation; and anti-inflammatory drugs.

 Beyond Antidepressants: Taking Stock of New Treatments