Astrocytes in the Ventromedial Hypothalamus Involve Chronic Stress-Induced Anxiety and Bone Loss in Mice

Chronic stress is one of the main risk factors of bone loss. While the neurons and neural circuits of the ventromedial hypothalamus (VMH) mediate bone loss induced by chronic stress, the detailed intrinsic mechanisms within the VMH nucleus still need to be explored. Astrocytes in brain regions play important roles in the regulation of metabolism and anxiety-like behavior through interactions with surrounding neurons. However, whether astrocytes in the VMH affect neuronal activity and therefore regulate chronic stress-induced anxiety and bone loss remain elusive. In this study, we found that VMH astrocytes were activated during chronic stress-induced anxiety and bone loss. Pharmacogenetic activation of the Gi and Gq pathways in VMH astrocytes reduced and increased the levels of anxiety and bone loss, respectively. Furthermore, activation of VMH astrocytes by optogenetics induced depolarization in neighboring steroidogenic factor-1 (SF-1) neurons, which was diminished by administration of N-methyl-D-aspartic acid (NMDA) receptor blocker but not by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor blocker. These results suggest that there may be a functional “glial-neuron microcircuit” in VMH nuclei that mediates anxiety and bone loss induced by chronic stress. This study not only advances our understanding of glial cell function but also provides a potential intervention target for chronic stress-induced anxiety and bone loss therapy.

Neuroinflammation in the normal-appearing white matter (NAWM) of the multiple sclerosis brain causes abnormalities at the nodes of Ranvier

Changes to the structure of nodes of Ranvier in the normal-appearing white matter (NAWM) of multiple sclerosis (MS) brains are associated with chronic inflammation. We show that the paranodal domains in MS NAWM are longer on average than control, with Kv1.2 channels dislocated into the paranode. These pathological features are reproduced in a model of chronic meningeal inflammation generated by the injection of lentiviral vectors for the lymphotoxin-α (LTα) and interferon-γ (IFNγ) genes. We show that tumour necrosis factor (TNF), IFNγ, and glutamate can provoke paranodal elongation in cerebellar slice cultures, which could be reversed by an N-methyl-D-aspartate (NMDA) receptor blocker. When these changes were inserted into a computational model to simulate axonal conduction, a rapid decrease in velocity was observed, reaching conduction failure in small diameter axons. We suggest that glial cells activated by pro-inflammatory cytokines can produce high levels of glutamate, which triggers paranodal pathology, contributing to axonal damage and conduction deficits.

Development of memantine as a drug for Alzheimer’s disease: A review of preclinical and clinical studies

Excitotoxicity contributes to neuronal cell death due to overstimulation of N-methyl-D-aspartate (NMDA) receptors by glutamate, which plays a significant role in the development and progression of Alzheimer’s disease (AD) and other neurodegenerative disorders. Studies have been conducted to identify a well-tolerated and selective NMDA receptor blocker in an effort to alleviate neurodegeneration. Memantine has been found to induce a distinct low-affinity NMDA receptor blockade in both preclinical and clinical studies Therefore, FDA approved this drug as a well-tolerated noncompetitive NMDA receptor blocker for treating moderate to severe cases of AD. Further, memantine showed neuroprotective effects in preclinical studies by selectively blocking excessive NMDA receptor activation. Altogether, this novel drug is well-tolerated and effective for treating moderate to severe AD in various clinical studies. This paper is a review of preclinical and clinical studies on the drug development process of memantine. Keywords: Memantine, Excitotoxicity, N-methyl-D-aspartate, Glutamate, Alzheimer’s disease, neurodegeneration

Madecassic Acid Reduces Fast Transient Potassium Channels and Promotes Neurite Elongation in Hippocampal CA1 Neurons

Background and Objective: Madecassic Acid (MA) is well known to induce neurite elongation. However, its correlation with the expression of fast transient potassium (AKv) channels during neuronal development has not been well studied. Therefore, the present study was designed to investigate the effects of MA on the modulation of AKv channels during neurite outgrowth. Methods: Neurite outgrowth was measured with morphometry software, and Kv4 currents were recorded by using the patch clamp technique. Results: The ability of MA to promote neurite outgrowth is dose-dependent and was blocked by using the mitogen/extracellular signal-regulated kinase (MEK) inhibitor U0126. MA reduced the peak current density and surface expression of the AKv channel Kv4.2 with or without the presence of NaN3. The surface expression of Kv4.2 channels was also reduced after MA treatment of growing neurons. Ethylene glycol tetraacetic acid (EGTA) and an N-methyl-D-aspartate (NMDA) receptor blocker, MK801 along with MA prevented the effect of MA on neurite length, indicating that calcium entry through NMDA receptors is necessary for MA-induced neurite outgrowth. Conclusion: The data demonstrated that MA increased neurite outgrowth by internalizing AKv channels in neurons. Any alterations in the precise density of ion channels can lead to deleterious consequences on health because it changes the electrical and mechanical function of a neuron or a cell. Modulating ion channel’s density is exciting research in order to develop novel drugs for the therapeutic treatment of various diseases of CNS.

Receptors, circuits and neural dynamics for prediction

SummaryLearned associations between stimuli allow us to model the world and make predictions, crucial for efficient behavior; e.g., hearing a siren, we expect to see an ambulance and quickly make way. While theoretical and computational frameworks for prediction exist, circuit and receptor-level mechanisms are unclear. Using high-density EEG, Bayesian modeling and machine learning, we show that trial history and frontal alpha activity account for reaction times (a proxy for predictions) on a trial-by-trial basis in an audio-visual prediction task. Predictive beta feedback activated sensory representations in advance of predicted stimuli. Low-dose ketamine, a NMDA receptor blocker – but not the control drug dexmedetomidine – perturbed predictions, their representation in higher-order cortex, and feedback to posterior cortex. This study suggests predictions depend on alpha activity in higher-order cortex, beta feedback and NMDA receptors, and ketamine blocks access to learned predictive information.

THE EFFECTIVENESS OF MEMANTINE ADMINISTRATON IN PATIENTS WITH NON-DEMENTIA COGNITIVE IMPAIRMENT. THE RESULTS OF A MULTICENTRE CLINICAL FOLLOW-UP STUDY

Memantine is a reversible N-methyl-D-a spartate (NMDA) receptor blocker. The paper reports the results of an investigation aimed at the assessment of memantine effectiveness, safety and tolerability in patients with non-dementia cognitive impairment. Two hundred and forty (240) patients were enrolled in this open-label, comparative, multicentre study. In these subjects cognitive disorders were less severe than dementia (MMSE score made up 22—27). Mean age was 69.2 + 5.7 years old. Among them 148 patients received acatinol memantine at a dosage of 20 mg daily within 6 months and 92 subjects comprised a comparison group. Memantine administration resulted in decreased severity of cognitive impairment, first of all due to the improvement of dysregulatory, mnestic and visual-spatial disorders. Besides, the treatment caused the alleviation of emotional disturbances. The degree of therapeutic effectiveness was independent from the presence or lack of cardiovascular diseases in the examined population. Further double-blind studies aimed at the assessment of memantine effectiveness in patients with non-dementia cognitive impairment are necessary.

T-817MA, but Not Haloperidol and Risperidone, Restores Parvalbumin-Positive γ-Aminobutyric Acid Neurons in the Prefrontal Cortex and Hippocampus of Rats Transiently Exposed to MK-801 at the Neonatal Period

The number of parvalbumin (PV)-positive γ-aminobutyric acid (GABA) neurons is decreased in the brain of rats transiently exposed to MK-801, an N-methyl-D-aspartate (NMDA) receptor blocker, in the neonatal stage (Uehara et al. (2012)). T-817MA [1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl} azetidin-3-ol maleate] is a neuroprotective agent synthesized for the treatment of psychiatric disorders characterized by cognitive disturbances, such as dementia. We herein sought to determine whether T-817MA, haloperidol (HPD), or risperidone (RPD) would ameliorate the decrease in the number of PV-positive GABA neurons in the medial prefrontal cortex (mPFC) and hippocampus of the model animals. Rats were treated with MK-801 (0.2 mg/kg/day) or vehicle on postnatal days (PD) 7–10, and the number of PV-positive neurons in the mPFC and hippocampus were measured on PDs 63. T-817MA (20 mg/kg), HPD (1 mg/kg), or RPD (1 mg/kg) were administered during PDs 49–62. Fourteen-day administration of T-817MA reversed the decrease in the number of PV-positive neurons in the above brain regions of rats given MK-801, whereas HPD and RPD were ineffective. These results indicate that T-817MA provides a novel pharmacologic strategy to enhance cognitive function in patients with schizophrenia.