Disrupted Myelin Protein Implicated in Schizophrenia

 Ask your competent? doctor how much your myelin was damaged in your stroke and the EXACT PROTOCOLS TO FIX THAT!  Doesn't know anything? Fire them!

myelin (77 posts to April 2011)

Disrupted Myelin Protein Implicated in Schizophrenia

Summary: A new study has identified the protein hnRNP A1 as a key player in the production and maintenance of myelin, the fatty sheath that insulates nerve fibers in the brain. Myelin loss is common in disorders like multiple sclerosis and schizophrenia, and this research shows that hnRNP A1 disruptions can impair myelination at the molecular level, even before behavioral symptoms appear.

Using a rodent model, scientists induced and later reversed demyelination to track the effects on memory, motor function, and social behavior. The findings offer fresh insight into how early molecular changes in myelin-related proteins could contribute to neurodegenerative and neuropsychiatric disorders, potentially opening new avenues for therapeutic intervention.

Key Facts:

• Myelin Disruption: Disruption of hnRNP A1 impairs myelin production and may play a role in schizophrenia and multiple sclerosis.
• Silent Molecular Shifts: Changes in myelin-related proteins occurred without immediate behavioral symptoms, suggesting early markers of disease.
• Reversibility Observed: Restoring myelin reversed behavioral deficits in rodents, underscoring therapeutic potential.

Source: FAPESP

Research published in the Journal of Neurochemistry has detailed the role of a protein, hnRNP A1, in the formation and stability of myelin, suggesting an important impact on neurodegenerative diseases and mental disorders such as multiple sclerosis and schizophrenia.

The findings pave the way for new research and potential treatments.

Myelin is a fatty substance produced by oligodendrocytes (cells of the central nervous system) that forms a sheath, like a kind of “insulator.”

It “protects” the extensions of neurons (axons) and increases the conduction speed of nerve impulses that carry information between neural cells.

Scientific literature has shown that patients with multiple sclerosis and schizophrenia lose myelin (called demyelination), leaving part of the axons “unplugged” and causing damage to brain function.

This rodent study examined changes in proteins essential for myelin production (myelination). The results highlight the involvement of hnRNP A1 in maintaining the integrity of this protective sheath.

hnRNP A1 regulates the processing of messenger RNA, i.e., it controls how the molecule is cut and assembled (splicing), thereby determining which proteins are produced and in what amounts. Studied for years by this group of scientists at the State University of Campinas (UNICAMP), in the state of São Paulo, Brazil, hnRNP A1 had already figured prominently in previous research carried out on brain tissue from people with schizophrenia and on cells grown in the laboratory.

“When I was a master’s student, I worked with oligodendrocyte predecessor cell lines and their responses to antipsychotics. This protein, hnRNP A1, always appeared. We decided to try to understand its role in oligodendrocytes.

“But to do this, we had to use an animal model to induce myelination and understand the process,” explains Caroline Brandão Teles, first author of the article and FAPESP doctoral fellow at the Institute of Biology (IB-UNICAMP).

For researcher Fernanda Crunfli, also from IB-UNICAMP and corresponding author of the paper, myelin has been an important target of study for neuropsychiatric diseases.

“We were able to analyze the demyelination process in the animals and then restore the myelin sheath. This allowed for an interesting study window.

“We did behavioral tests to assess locomotion, short- and long-term memory, and social interaction. When the myelin is restored, all these functions return to the brain,” says Crunfli, who was a FAPESP postdoctoral fellow.

Teles points out that this was one of the results that caught the group’s attention – the fact that the changes were detected at the molecular level, without affecting the animals’ behavior.

“With this molecular and non-behavioral alteration, the work has the interesting potential to pinpoint an important protein in the establishment of schizophrenia. This same animal model is analyzed in research on multiple sclerosis, for example, and when there’s a behavioral study, changes are noted.

“In the case of schizophrenia, the fact that the behavior isn’t altered indicates, in my opinion, that this protein is essential in the development of the disease and may have an influence on its genesis,” Professor Daniel Martins-de-Souza, from IB-UNICAMP, Teles’ supervisor and head of the Neuroproteomics Laboratory, told Agência FAPESP.

Schizophrenia is a mental disorder characterized by loss of contact with reality (psychosis), hallucinations, delusions, and impaired cognition, among other symptoms. The exact cause is still unknown, but recent research suggests a combination of hereditary factors and molecular and functional alterations in the brain. Treatment includes antipsychotic medications and psychotherapy.

It is estimated that approximately 1.6 million people in Brazil have schizophrenia. Worldwide, the prevalence is about 1% of the world’s population.

For years, Martins-de-Souza’s research group has been working to understand the role of oligodendrocytes in schizophrenia and has managed to map a series of brain proteins that help to unravel the molecular basis of the disorder.

To understand the research

The group used a rodent (murine) model that has also been studied in cases of multiple sclerosis, a disease characterized by severe demyelination.

From the eighth week of the experiment, demyelination was induced and continued for another five weeks. The process was then interrupted and the myelin sheath was restored.

During this time, the researchers analyzed the activity of hnRNP A1. “We saw that the proteins linked to myelin in these animals were all reduced. By disrupting the activity of this protein [hnRNP A1], we ended up disrupting myelination,” says Teles.

The scientists believe that studying the impact of the protein’s alterations on synaptic transmission and cognitive processes could reveal new therapeutic targets.

Funding: In addition to the grants, the research was also supported by FAPESP through six other projects (17/25588-1, 19/05155-9, 18/01410-1, 23/08885-3, 18/01669-5 and 23/11514-7).

About this schizophrenia research news

Author: Heloisa Reinert
Source: FAPESP
Contact: Heloisa Reinert – FAPESP
Image: The image is credited to Neuroscience News

Original Research: Open access.
“Impacts of hnRNP A1 Splicing Inhibition on the Brain Remyelination Proteome” by Caroline Brandão Teles et al. Journal of Neurochemistry

Memory Enhancement with Kynurenic Acid and its Mechanisms in Neurotransmission

 This will require lots of human testing. Low levels of  KYNA  lead to Alzheimer’s and Parkinson’s while high levels lead to schizophrenia. I wouldn't want to be in this clinical trial if the range is that delicate.

Memory Enhancement with Kynurenic Acid and its Mechanisms in Neurotransmission

Diána Martos 1, Bernadett Tuka 1, Masaru Tanaka 1, László Vécsei 1,2,*, and Gyula Telegdy 3 1 MTA-SZTE Neuroscience Research Group, Hungarian Academy of Sciences-University of Szeged (MTASZTE), Semmelweis u. 6, Szeged, H-6725 Hungary 2 Department of Neurology, Albert Szent-Györgyi Medical School, University of Szeged, Semmelweis u. 6, H6725 Szeged, Hungary 3 Department of Pathophysiology, Albert Szent-Györgyi Medical School, University of Szeged, Semmelweis u. 5, H-6725 Szeged, Hungary * Correspondence: vecsei.laszlo@med.u-szeged.hu; Tel.: +36 62 342 361 

Abstract: 

Kynurenic acid (KYNA) is an endogenous tryptophan (Trp) metabolite known to possess neuroprotective property. KYNA plays critical roles in nociception, neurodegeneration, and neuroinflammation. A lower level of KYNA is observed in patients with neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases or psychiatric disorders such as depression and autism spectrum disorders, whereas a higher level of KYNA is associated with the pathogenesis of schizophrenia. Little is known about the optimal concentration for neuroprotection and the threshold for neurotoxicity. In this study the effects of KYNA on memory functions were investigated by passive avoidance test in mice. Six different doses of KYNA were administered intracerebroventricularly to previously trained CFLP mice and they were observed following 24 hours. High doses of KYNA (i.e., 20-40 μg/2 μl) significantly decreased the avoidance latency, whereas a low dose of KYNA (0.5 μg/2 μl) significantly elevated it compared with controls, suggesting that the low dose of KYNA enhanced memory function. Furthermore, six different receptor blockers were applied to reveal the mechanisms underlying the memory enhancement induced by KYNA. The series of tests revealed the possible involvement of the serotonergic, dopaminergic, α and β adrenergic, and opiate systems in the nootropic effect. The study confirmed that a low dose of KYNA improved a memory component of cognitive domain, which was mediated by, at least in part, four systems of neurotransmission in an animal model of learning and memory. Keywords: tryptophan; kynurenine; kynurenic acid; passive avoidance; cognitive domain; memory; cognitive enhancer; neurotransmission; receptor blockers; translational 1. Introduction Worldwide, around 50 million people suffer from major neurocognitive disorders. Alzheimer’s disease (AD) represents 60-70 percent of cases, imposing a physical, psychological, social, and economic burden on the elderly, their families, caregivers as well as society [1]. Patients who develop AD first demonstrate a subtle decline in memory and learning, followed by changes in executive cognitive function and in language and visuospatial processing; indeed, recent evidence suggests that impairments in the ability to process contextual information and in the regulation of responses to threat are related to structural and physiological alterations in the prefrontal cortex (PFC) and medial temporal lobe, addressing how this progressive brain deterioration can eventually cause patterns of cognitive dysfunctions observed in patients with AD [2]. The cause of major neurocognitive disorders remains unknow, but it is considered to be caused by convergence of multifactorial factors including genetic, environmental, infectious, and nutritional components, and lifestyle, among others [3,4]. There is no remedy for neurodegenerative diseases. Disease-modifying and symptom-relieving measures are mainstays of treatment. Thus, a tremendous effort has been made to identify pathomechanisms, discover interventional targets, and design novel pharmaceutical agents [5]. 

KYNA is a metabolite of the Trp-kynurenine (KYN) metabolic system, known to possess neuroprotective property [6Encyclopedia]. The neuroprotective activities are considered to be attributed to the antagonism of the excitatory amino acid receptors (EAARs) such as the N-methyl-D-aspartate (NMDA) receptor, the α-amino-3-hydroxy-5-methyl-4- isoxazole propionic acid (AMPA) receptor, and the kainic acid receptor [7-10]. Furthermore, KYNA acts as an agonist of the G-protein-coupled receptor 35 (GPR35) and the aryl hydrocarbon receptor (AHR) [11-14]. In addition, opioid receptors are presumed to be interacting partners of KYNA [15,16]. It was previously postulated that the main component of KYNA-induced inhibition in glutamatergic neurotransmission may attribute to non-competitive inhibition of α7- nicotinic acetylcholine receptors at glutamatergic presynaptic axon terminals [17], thereby regulating the release of glutamate. However, these results could not be reproduced by four different, independent groups subsequently. Thus, it is still questionable that KYNA may affect glutamate release via the mechanism [18-22]. KYNA plays crucial roles in the regulation of the intracellular Ca2+ and mitochondrial dysfunction-induced neuronal cell death in conditions associated with excitotoxicity (Fig. 1). Figure 1. KYNA influences the neuronal and glial glutamatergic neurotransmission. Recently, KYNA and its novel pharmacokinetically favorable analogues demonstrated beneficial effects in animal models of neurologic diseases including pathologic pain sensation, migraine, ischemic stroke, and epilepsy, neurodegenerative diseases, and psychiatric disorder including depression, anxiety, and addiction [23-39]. Accordingly, neuroprotective KYN metabolites, their analogues, the inhibition of Trp-KYN enzymes which are responsible for production of toxic metabolites, their use for biomarkers, and its interaction with adjacent biosystems are under extensive research [40-48]. The beneficial effects were detected when these molecules were peripherally administered in an acute or semi-chronic manner with relatively high (millimolar) concentrations. Lower levels of KYNA were observed in patients with neurodegenerative diseases and psychiatric disorders [3,6,32,49]. Those illnesses are generally characterized by alterations in inflammatory mediators and mu-opioid receptor, and increased levels in neurotoxic Try-KYN metabolites, which, furthermore, lead to changes in the amygdala [50]. However, Manipulations to elevate KYNA levels have a potential risk of interfering with cognitive functions. Indeed, elevated levels of KYNA in the brain or its chronic application in higher doses are known to evoke cognitive impairment by inhibiting predominantly the glutamatergic system, a phenomenon having been linked to the pathophysiology of AD [51]. Furthermore, prenatal exposure of high levels of KYNA has also been experimentally shown to be associated with sustained cognitive deficits, with implications to schizophrenia [52,53]. Therefore, it is essential to identify the doses of KYNA and KYNArelated molecules to provide neuroprotection without any associated cognitive side effects. In humans, KYNA is robustly synthesized in the endothelium and its serum levels correlate with homocysteine, a risk factor for cognitive decline: recent studies have suggested that a selective hippocampal increase of the KYNA level may be an important factor contributing to KYNA-related cognitive impairment. Identifying the mechanisms by which high KYNA levels in the hippocampal area may contribute to the deterioration of cognition would provide insight that might be used to manage inflammation-associated mental health disorders, including the discovery of new diagnostic and treatment therapies for depression: recently, several studies have suggested the effectiveness of non-invasive brain simulation (NIBS) to interfere and modulate the abnormal activity of neural circuits including the amygdala-mPFC-hippocampus, involved in the acquisition and consolidation of memories, which are altered in psychiatric disorders, such as fear-related disorder including anxiety disorder, phobias, posttraumatic stress disorder, or depression [54,55]. Our previous studies did not detect any behavior impairment of animals when they were treated intraperitoneally (i.p.) with millimolar doses of KYNA or its analogues [23,56]. The administration of KYNA and its analogues increased inducibility of long-term potentiation (LTP) in the CA1 region in rats, indicating better hippocampal function [57]. However, few data are available on the effects of a low dose KYNA. It was reported that KYNA has a dose-dependent dual action on AMPA receptors: the nanomolar and micromolar concentrations of KYNA could facilitate the responses of AMPA receptors via modulating their desensitization, whereas the millimolar doses of this compound antagonized these receptors [58]. It was demonstrated that KYNA was able to reduce the amplitudes of the field excitatory postsynaptic potentials (EPSPs) in hippocampal slices of young rats at micromolar concentrations, whereas the nanomolar concentrations evoked stimulation. Therefore, KYNA as a 'Janus-faced' molecule may display different effects according to its concentration by acting on different receptors and through mechanisms [59]. A lower endogenous formation of KYNA induce positive effects in the cognition. Indeed, the role of the kynurenine aminotransferase II (KAT II), an enzyme responsible for the endogenous KYNA synthesis in the human brain, has been recently emphasized in the mechanisms of memory; activities of KAT I and II showed age-dependent increase with an exception for KAT II in the frontal cortex, which could be related to functional alterations in the PFC reported in psychiatric and brain-damaged patients’ memory and learning abilities. Furthermore, recent studies revealed that naturally occurring bilateral lesions in the human ventromedial PFC compromise the capacity of associative learning [60,61], suggesting that PFC dysfunctions cause impairment of aversive learning and emotional memory circuits, which might be transversal across many psychiatric disorders in humans. Pharmacological inhibition or genetic ablation of KAT II reduced KYNA levels in the brain and improved the performance in working/spatial memory and sustained attention tasks in different animal models [62-64]. The inhibition of KAT II, with a subsequent reduction of an endogenous KYNA level restores normal cognitive function and thus, a manipulation of KYNA levels may be a promising therapeutic target in cognitive impairment associated with elevated concentrations of KYNA in the brain.

 

More at link.

Enhancement of hippocampal neurogenesis by lithium

This is in rodents so don't start bugging your doctor that you need lithium. Unless maybe you are already taking this for bipolar or Schizophrenia.
http://www.ncbi.nlm.nih.gov/pubmed/10987856 

Chen G¹, Rajkowska G, Du F, Seraji-Bozorgzad N, Manji HK.

Author information

Abstract

Increasing evidence suggests that mood disorders are associated with a reduction in regional CNS volume and neuronal and glial cell atrophy or loss. Lithium, a mainstay in the treatment of mood disorders, has recently been demonstrated to robustly increase the levels of the cytoprotective B-cell lymphoma protein-2 (bcl-2) in areas of rodent brain and in cultured cells. In view of bcl-2's antiapoptotic and neurotrophic effects, the present study was undertaken to determine if lithium affects neurogenesis in the adult rodent hippocampus. Mice were chronically treated with lithium, and 5-bromo-2-deoxyuridine (BrdU) labeling of dividing cells was conducted over 12 days. Immunohistochemical analysis was undertaken 1 day after the last injection, and three-dimensional stereological cell counting revealed that lithium produced a significant 25% increase in the BrdU-labeled cells in the dentate gyrus. Double-labeling immunofluorescence studies were undertaken to co-localize BrdU-positive cells with neuron-specific nuclear protein and showed that approximately 65% of the cells were double-labeled. These results add to the growing body of evidence suggesting that mood stabilizers and antidepressants exert neurotrophic effects and may therefore be of use in the long-term treatment of other neuropsychiatric disorders.

Can a Failed Schizophrenia Drug Prevent PTSD?

What does your doctor think about this for your chances of getting PTSD post-stroke?
http://neurocritic.blogspot.com/2014/07/can-failed-schizophrenia-drug-prevent.html

Efficacy of anti-inflammatory agents to improve symptoms in patients with schizophrenia: an update

A question for your doctor. What inflammation has occurred in your post-stroke brain and what the hell are you doing about it?
At least someone is studying this for other brain diseases.
Efficacy of anti-inflammatory agents to improve symptoms in patients with schizophrenia: an update