Impact of Pharmacological and Non-Pharmacological Modulators on Dendritic Spines Structure and Functions in Brain.

Dendritic spines are small, thin, hair-like protrusions found on the dendritic processes of neurons. They serve as independent compartments providing large amplitudes of Ca2+ signals to achieve synaptic plasticity, provide sites for newer synapses, facilitate learning and memory. One of the common and severe complication of neurodegenerative disease is cognitive impairment, which is said to be closely associated with spine pathologies viz., decreased in spine density, spine length, spine volume, spine size etc. Many treatments targeting neurological diseases have shown to improve the spine structure and distribution. However, concise data on the various modulators of dendritic spines are imperative and a need of the hour. Hence, in this review we made an attempt to consolidate the effects of various pharmacological (cholinergic, glutamatergic, GABAergic, serotonergic, adrenergic, and dopaminergic agents) and non-pharmacological modulators (dietary interventions, enriched environment, yoga and meditation) on dendritic spines structure and functions. These data suggest that both the pharmacological and non-pharmacological modulators produced significant improvement in dendritic spine structure and functions and in turn reversing the pathologies underlying neurodegeneration. Intriguingly, the non-pharmacological approaches have shown to improve intellectual performances both in preclinical and clinical platforms, but still more technology-based evidence needs to be studied. Thus, we conclude that a combination of pharmacological and non-pharmacological intervention may restore cognitive performance synergistically via improving dendritic spine number and functions in various neurological disorders.

Role of Glutamatergic System in Obsessive-Compulsive Disorder with Possible Therapeutic Implications.

Obsessive-compulsive disorder (OCD) is a chronic psychiatric illness and 1 of the most common anxiety disorders with the prevalence of 3%. Although its pathogenesis remains unclear, the traditional model focused on alternations in the serotonin system. Selective serotonin reuptake inhibitors provide the most effective treatment; however, as much as 40-60% of patients do not respond to antidepressants therapy. Thus, attention has shifted towards other neurotransmitter systems and related neuroanatomical structures. Recently, there is extensive evidence showing a key role of glutamate pathways abnormalities within the cortico-striatal-thalamo-cortical circuitry and temporal lobes in OCD pathogenesis. In this review, we link together the existent neuroanatomical, neurophysiological, and neuropsychological evidence to argue for potential benefits of adjuvant treatment with glutamatergic agents, especially memantine. By a targeted de-excitation effect on the glutamatergic system in the temporal lobes and connected brain regions, memantine might further alleviate OCD symptoms. This effect should be even more pronounced in certain subtypes of patients with specific cognitive deficits and maladaptive compensatory memory processes (e.g., checkers).

Emerging Treatments in Schizophrenia: Highlights from Recent Supplementation and Prevention Trials.

In this column we examine the recent literature regarding adjunctive antipsychotic treatment of schizophrenia. We provide a brief introduction outlining the urgent need for new therapeutics, particularly for the treatment of negative and cognitive symptoms of schizophrenia. We then address (by mechanism of action) the most extensively studied adjunctive antipsychotic treatments. We conclude that adjunctive treatments targeting glutamatergic modulation, as well as supplementation with certain vitamins, have the strongest evidence for use in the treatment of schizophrenia. Further, larger randomized, controlled trials are needed, focusing on certain subgroups of patients and specific antipsychotic medications.

Therapeutic strategies to prevent and manage dyskinesias in Parkinson's disease.

INTRODUCTION: Chronic treatment with levodopa is associated with the development of motor fluctuations and dyskinesias particularly in young Parkinson patients. In some cases, dyskinesias become so severe that they interfere with normal movement and negatively impact quality of life. AREAS COVERED: In this review, we discuss benefits and limits of available therapeutic approaches aimed at delaying or managing dyskinesias as well as new strategies that are currently under investigation. EXPERT OPINION: Among available treatments, monotherapy with dopamine agonists in the early phases of the disease reduces the risk for dyskinesias compared with levodopa. Nevertheless, dopamine agonists are unable to prevent dyskinesias once levodopa is added, which is always required once disease severity progresses. Convincing evidence of dyskinesia improvement has been shown only for deep brain stimulation and to some extent also for duodenal levodopa infusion and subcutaneous apomorphine. These approaches are expensive, have restrictive inclusion criteria and can cause potentially serious side effects. Alternative therapies include drugs targeting nondopaminergic neurotransmitter systems. Amantadine improves dyskinesias but its long-term effect is often unsatisfactory. Glutamatergic and gabaergic compounds have been tested in clinical trials, with promising results. By contrast, adrenergic drugs, fipamezole and idazoxan, did not show antidyskinetic effect.

mGlu2/3 agonist-induced hyperthermia: an in vivo assay for detection of mGlu2/3 receptor antagonism and its relation to antidepressant-like efficacy in mice.

An assay to detect the on-target effects of mGlu2/3 receptor antagonists in vivo would be valuable in guiding dosing regimens for the exploration of biological effects of potential therapeutic import. Multiple approaches involving blockade of mGlu2/3 receptor agoinist-driven behavioral effects in mice and rats were investigated. Most of these methods failed to provide a useful method of detection of antagonists in vivo (e.g., locomotor activity). In contrast, the mGlu2/3 receptor agonist LY379268 produced dose-dependent increases in body temperature of mice. The hyperthermic effects of LY379268 was abolished in mGlu2 and in mGlu2/3 receptor null mice but not in mGlu3 null mice. Hyperthermia was not produced by an mGlu8 receptor agonist. Agonist-induced hyperthermia was prevented in a dose-dependent manner by structurally-distinct mGlu2/3 receptor antagonists. The blockade was stereo-specific. Moreover, this biological readout was responsive to both orthosteric and to negative allosteric modulators of mGlu2/3 receptors. Antagonism of agonist-induced hyperthermia predicted antidepressant-like efficacy in the mouse forced swim test. As with the hyperthermic response, the antidepressant-like effects of mGlu2/3 receptor antagonists were shown to be due to mGlu2 and not to mGlu3 or mGlu8 receptors through the use of receptor knock-out mice. The ability to rapidly assess on-target activity of mGlu2/3 receptor antagonists enables determination of parameters for setting efficacy doses in vivo. In turn, efficacy-related data in the preclinical laboratory can help to set expectations of therapeutic potential and dosing in humans.

The glutamatergic system and Alzheimer's disease: therapeutic implications.

Alzheimer's disease affects nearly 5 million Americans currently and, as a result of the baby boomer cohort, is predicted to affect 14 million Americans and 22 million persons totally worldwide in just a few decades. Alzheimer's disease is present in nearly half of individuals aged 85 years. The main symptom of Alzheimer's disease is a gradual loss of cognitive function. Glutamatergic neurotransmission, an important process in learning and memory, is severely disrupted in patients with Alzheimer's disease. Loss of glutamatergic function in Alzheimer's disease may be related to the increase in oxidative stress associated with the amyloid beta-peptide that is found in the brains of individuals who have the disease. Therefore, therapeutic strategies directed at the glutamatergic system may hold promise. Therapies addressing oxidative stress induced by hyperactivity of glutamate receptors include supplementation with estrogen and antioxidants such as tocopherol (vitamin E) and acetylcysteine (N-acetylcysteine). Therapy for hypoactivity of glutamate receptors is aimed at inducing the NMDA receptor with glycine and cycloserine (D-cycloserine). Recently, memantine, an NMDA receptor antagonist that addresses the hyperactivity of these receptors, has been approved in some countries for use in Alzheimer's disease.