scholarly journals TrkB Agonist LM22A-4 Increases Oligodendroglial Populations During Myelin Repair in the Brain

2019 ◽  
Author(s):  
Huynh TH Nguyen ◽  
Rhiannon J Wood ◽  
Alexa R Prawdiuk ◽  
Sebastian GB Furness ◽  
Junhua Xiao ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Pharmacokinetic Profile ◽  
Dependent Manner ◽  
Sheath Thickness ◽  
Beneficial Effects ◽  
Central Demyelination ◽  
Cns Myelination ◽  
Trk B ◽  
The Brain ◽  
Myelin Sheath Thickness

AbstractThe neurotrophin, brain-derived neurotrophic factor (BDNF) promotes central nervous system (CNS) myelination during development and after injury. This is achieved via activation of oligodendrocyte-expressed tropomyosin-related kinase (Trk) B receptors. However, while administration of BDNF has shown beneficial effects, BDNF itself has a poor pharmacokinetic profile. Here, we compare two TrkB-targeted BDNF-mimetics, the structural-mimetic, tricyclic dimeric peptide-6 (TDP6) and the non-peptide small molecule TrkB agonist LM22A-4 in the cuprizone model of central demyelination in female mice. Both mimetics promoted remyelination, increasing myelin sheath thickness and oligodendrocyte densities after one-week recovery. Importantly, LM22A-4 exerts these effects in an oligodendroglial TrkB-dependent manner. However, analysis of TrkB signaling by LM22A-4 suggests rather than direct activation of TrkB, LM22A-4 exerts its effects via indirect transactivation of Trk receptors. Overall, these studies support the therapeutic strategy to selectively targeting TrkB activation to promote remyelination in the brain.

scholarly journals Glutamate and γ-aminobutyric acid differentially modulate glymphatic clearance of amyloid β through pulsation- and aquaporin-4 dependent mechanisms

2020 ◽  
Author(s):  
Cheng Wu ◽  
Yi-wei Feng ◽  
Qun Zhang ◽  
Feng-yin Liang ◽  
Yue Lan ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Amyloid Β ◽  
Aquaporin 4 ◽  
Aminobutyric Acid ◽  
Dependent Manner ◽  
Ang Ii ◽  
Induced Hypertension ◽  
Effective Therapeutic Strategy ◽  
Glymphatic Pathway ◽  
The Brain

AbstractThe glymphatic system contributes to a large proportion of brain waste clearance, including removal of amyloid β (Aβ). We have demonstrated that glutamate and γ-aminobutyric acid (GABA) influence glymphatic clearance through distinct mechanisms whereby GABA exerts modulatory effects in an aquaporin-4 (AQP4)-dependent manner while the actions of glutamate are pulsation-dependent. The efficacy of GABA and glutamate in alleviating Aβ in APP-PS1 and Angiotensin-II (Ang-II) induced hypertension mouse models was further evaluated. Notably, increasing GABA or inhibiting glutamate levels led to reduced binding of Aβ to pre-labeled plaques to similar extents in APP-PS1 mice while GABA appeared more efficient in Aβ clearance in hypertensive animals than the glutamate inhibitor. Our findings support the modulation of neurotransmitters that influence the glymphatic pathway via distinct mechanisms as a potentially effective therapeutic strategy for clearance of Aβ deposits from the brain.

scholarly journals Neuregulin 1 type III reduces severity in a mouse model of Congenital Hypomyelinating Neuropathy

2018 ◽  
Author(s):  
Belin Sophie ◽  
Francesca Ornaghi ◽  
Ghjuvan'Ghjacumu Shackleford ◽  
Jie Wang ◽  
Cristina Scapin ◽  
...  
Keyword(s):  
Mouse Model ◽  
Cell Fate ◽  
Action Potentials ◽  
Sheath Thickness ◽  
Neuregulin 1 ◽  
Type Iii ◽  
Beneficial Effects ◽  
Axonal Protein ◽  
Congenital Hypomyelinating Neuropathy ◽  
Myelin Sheath Thickness

Myelin sheath thickness is precisely regulated and essential for rapid propagation of action potentials along myelinated axons. In the peripheral nervous system, extrinsic signals from the axonal protein neuregulin 1 type III regulate Schwann cell fate and myelination. Here we ask if modulating neuregulin 1 type III levels in neurons would restore myelination in a model of congenital hypomyelinating neuropathy (CHN). Using a mouse model of CHN, we rescued the myelination defects by early overexpression of neuregulin 1 type III. Surprisingly, the rescue was independent from the upregulation of Egr2 or essential myelin genes. Rather, we observed the activation of MAPK/ERK and other myelin genes such as peripheral myelin protein 2 (Pmp2) and oligodendrocyte myelin glycoprotein (Omg). We also confirmed that the permanent activation of MAPK/ERK in Schwann cells has detrimental effects on myelination. Our findings demonstrate that the modulation of axon-to-glial neuregulin 1 type III signaling has beneficial effects and restores myelination defects during development in a model of CHN.

scholarly journals Far Infrared Light Irradiation Enhances Microglial Aβ Clearance and Ameliorates Cognitive Deficit in Alzheimer’s Disease-Like Mice

2020 ◽  
Author(s):  
Qingyong Li ◽  
Wensi Wu ◽  
Yanan Lu ◽  
Jing Wen ◽  
Jiaoyan Ren ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Memory Impairment ◽  
Therapeutic Strategy ◽  
Cognitive Deficit ◽  
Far Infrared ◽  
Light Treatment ◽  
Infrared Light ◽  
Beneficial Effects ◽  
The Brain

Abstract BackgroundExposure to sunlight may decrease the risk of developing Alzheimer’s disease (AD). However, the wavelength of the light with this therapeutic effect and the related mechanism remain elusive. MethodWe evaluated the behaviors of AD-like mice treated by light of different wavelengths and showed that far infrared (FIR) light (λ = 3 - 25 μm) had a great potential in ameliorating cognition dysfunction. ResultsFIR light treatment promoted the recruitment of microglia to Aβ plaques, enhanced the phagocytosis of Aβ and decreased neuroinflammatory responses. Thus, FIR light treatment had a broad spectrum of beneficial effects on the brain, including alleviating the Aβ burden and neuroinflammation. ConclusionsAs a result, FIR light treatment ameliorates the learning and memory impairment in AD-like mice. Our findings uncovered a previously unappreciated function of FIR light, suggesting that FIR light treatment may be a potential therapeutic strategy for AD.

scholarly journals Review of Kyotorphin Research: A Mysterious Opioid Analgesic Dipeptide and Its Molecular, Physiological, and Pharmacological Characteristics

2021 ◽  
Vol 3 ◽  
Author(s):  
Hiroshi Ueda
Keyword(s):  
Transient Receptor Potential ◽  
Opioid Analgesic ◽  
Receptor Potential ◽  
Underlying Mechanism ◽  
Peptide Transporter ◽  
Dependent Manner ◽  
Beneficial Effects ◽  
The Future ◽  
Design Function ◽  
The Brain

Tyrosine-arginine (kyotorphin), an opioid analgesic dipeptide, was discovered more than 40 years ago in 1979. The evidence accumulated during this period has established the physiological significance of kyotorphin as a neuromodulating peptide, and pharmacological applications. Some of the following important findings have been discussed in this review: (1) kyotorphin is unevenly distributed in the brain; it is found in high concentrations in the pain pathway, which involves the regions associated with morphine analgesia; (2) kyotorphin is subcellularly localized in the synaptosome fraction or nerve-ending particles; (3) a specific synthetase generates kyotorphin from tyrosine and arginine; (4) kyotorphin may be also processed from calpastatin by a novel calcium-activated neutral protease or calpain; (5) kyotorphin preloaded into the synaptosome is released by high K+ depolarization in a Ca2+-dependent manner; (6) kyotorphin has a specific G protein coupled receptor, which mediates the activation of phospholipase C (PLC) and inhibition of adenylyl cyclase through Gi; (7) leucine-arginine works as a specific kyotorphin receptor antagonist; 8) membrane-bound aminopeptidase or excretion through a peptide transporter, PEPT2, may contribute to the inactivation of kyotorphin; and (9) kyotorphin causes increased Met-enkephalin release from brain and spinal slices. It is also known that the opening of plasma membrane Ca2+ channels through a conformational coupling of the InsP3 receptor with the transient receptor potential C1, which is downstream of the kyotorphin receptor-mediated activation of Gi and PLC, could be a potential underlying mechanism of Met-enkephalin release. Considering these findings, translational research is an exciting domain that can be explored in the future. As kyotorphin is a small molecule, we could design function-added kyotorphin derivatives. These studies would include not only the brain-permeable kyotorphin derivatives but also hybrid kyotorphin derivatives conjugated with small compounds that have additional pharmacological actions. Further, since there are reports of kyotorphin being involved in either the etiology or treatment of Alzheimer's disease, epilepsy, inflammation, and chronic pain, studies on the beneficial effects of kyotorphin derivatives should also be expected in the future.

CALCULATING MYELIN SHEATH THICKNESS WITH WATERSHED ALGORITHM FOR BIOLOGICAL ANALYSIS

2016 ◽  
Vol 78 (5-6) ◽  
Author(s):  
Kenneth Huang ◽  
Yunxia Ji ◽  
Steed Huang ◽  
Qi Chen
Keyword(s):  
Electron Microscope ◽  
Mixed Method ◽  
Brain Cell ◽  
Watershed Algorithm ◽  
Sheath Thickness ◽  
Medical Diagnostic ◽  
Myelin Thickness ◽  
The Brain ◽  
Scanning Electron ◽  
Myelin Sheath Thickness

In this paper, the brief reviews of the significance of the myelin thickness to various root courses of the diseases for a human being, and the similarities between the human and the lab mouse being researched extensively so far are presented. Once we establish the necessity for a biological statistical analysis of the myelin thickness with regard to the particular category of the brain cell, we can then develop a mixed algorithm based on the watershed principle and the binaryzation principle that can be used to automatically process the scanning electron microscope pictures in batches. The initial analysis does indicate that the mixed method improved efficiency of data processing while not overlooking some important medical diagnostic factors.  

Impact of Cannabis-Based Medicine on Alzheimer’s Disease by Focusing on the Amyloid β-Modifications: A Systematic Study

2020 ◽  
Vol 19 (5) ◽  
pp. 334-343
Author(s):  
Tahereh Farkhondeh ◽  
Haroon Khan ◽  
Michael Aschner ◽  
Fariborz Samini ◽  
Ali M. Pourbagher-Shahri ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Studies ◽  
Therapeutic Strategy ◽  
Amyloid Β ◽  
Inclusion Criteria ◽  
Beneficial Effects ◽  
Ovid Medline ◽  
Based Medicine ◽  
The Brain

Deposition of Amyloid-beta (Aβ) peptide in the brain is the leading source of the onset and progression of Alzheimer’s Disease (AD). Recent studies have suggested that anti-amyloidogenic agents may be a suitable therapeutic strategy for AD. The current review was proposed to address the beneficial effects of cannabis-based drugs for the treatment of AD, focusing primarily on Aβ modifications. Keywords related to AD, Aβ, and cannabis-based on MeSH were identified and were searched in PubMed, Google Scholar, Scopus, Ovid-Medline, and Web of Science from inception until 15 March 2020. The full text of identified papers was obtained and assessed based on exclusion and inclusion criteria. The review is based on articles that have focused on AD and the amyloidogenic pathway. A total of 17 studies were identified based on the inclusion criteria; however, nine studies qualified for this systematic review. The maximum and minimum cannabis dosages, mostly CBD and THC in animal studies, were 0.75 and 50 mg/kg, respectively. Cannabis (CBD and THC) was injected for 10 to 21 days. The findings of the 9 articles indicated that cannabis-based drugs might modulate A. modifications in several AD models. Our findings establish that cannabis-based drugs inhibited the progression of AD by modulating Aβ modifications.

scholarly journals Targeting TrkB with a brain-derived neurotrophic factor mimetic promotes myelin repair in the brain

2018 ◽  
Author(s):  
Jessica L Fletcher ◽  
Rhiannon J Wood ◽  
Jacqueline Nguyen ◽  
Eleanor ML Norman ◽  
Christine MK Jun ◽  
...  
Keyword(s):  
Myelin Sheath ◽  
Neurotrophic Factor ◽  
Brain Derived Neurotrophic Factor ◽  
Demyelinating Diseases ◽  
Sheath Thickness ◽  
Oligodendrocyte Differentiation ◽  
Trkb Receptors ◽  
The Brain ◽  
Myelin Sheath Thickness

AbstractMethods to promote myelin regeneration in response to central myelin loss are essential to prevent the progression of clinical disability in demyelinating diseases. The neurotrophin brain-derived neurotrophic factor (BDNF) is known to promote myelination during development via oligodendrocyte expressed TrkB receptors. Here, we use a structural mimetic of BDNF to promote myelin regeneration in a preclinical mouse model of central demyelination. We show that selective targeting of TrkB with the BDNF-mimetic enhances remyelination, increasing oligodendrocyte differentiation, the frequency of myelinated axons, and myelin sheath thickness after a demyelinating insult. Treatment with exogenous BDNF exerted an attenuated effect, increasing myelin sheath thickness only. Further, following conditional deletion of TrkB from pre-myelinating oligodendrocytes, we show the effects of the BDNF-mimetic on oligodendrocyte differentiation and remyelination are lost, indicating these are dependent on oligodendrocyte expression of TrkB. Overall, these studies demonstrate that targeting oligodendrocyte TrkB promotes in vivo remyelination in the brain.

scholarly journals Naringin Supplementation during Pregnancy Induces Sex and Region-Specific Alterations in the Offspring’s Brain Redox Status

2021 ◽  
Vol 18 (9) ◽  
pp. 4805
Author(s):  
Bernardo Gindri dos Santos ◽  
Caroline Peres Klein ◽  
Mariana Scortegagna Crestani ◽  
Rafael Moura Maurmann ◽  
Régis Mateus Hözer ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Prefrontal Cortex ◽  
Wistar Rats ◽  
Redox Status ◽  
Disease Models ◽  
Dependent Manner ◽  
Beneficial Effects ◽  
Sensitive Periods ◽  
The Brain

Research has shown the beneficial effects of naringin supplementation to adult rodents, which can ameliorate oxidative stress in disease models. However, evidence has demonstrated that polyphenol supplementation induced detrimental effects when consumed during sensitive periods of development, such as pregnancy. Therefore, we investigated the effect of maternal naringin supplementation during pregnancy on the offspring’s cerebral redox status. Pregnant Wistar rats were divided into control and naringin groups and supplemented from gestational day 15 to gestational day 21. On postnatal days 1, 7, and 21, offspring were euthanized, and the prefrontal cortex, hippocampus, striatum, and cerebellum dissected. On postnatal day 1, maternal naringin supplementation positively modulated the pups’ brain redox status. On postnatal day 7, a pro-oxidative milieu was observed in the offspring’s striatum and cerebellum in a sex-dependent manner, even though the prefrontal cortex and hippocampus were not negatively affected. Besides, the alterations observed on postnatal day 7 did not persist up to weaning. Our findings demonstrated that the effect induced by naringin supplementation in the brain redox status differed according to the period of development in which naringin was consumed since the beneficial effects usually found in the adult rodents became detrimental when the supplementation was applied during pregnancy.

Therapeutic Approaches to Alzheimer’s Type of Dementia: A Focus on FGF21 Mediated Neuroprotection

2019 ◽  
Vol 25 (23) ◽  
pp. 2555-2568 ◽  
Author(s):  
Rajeev Taliyan ◽  
Sarathlal K. Chandran ◽  
Violina Kakoty
Keyword(s):  
Diabetes Mellitus ◽  
Protein Trafficking ◽  
Metabolic Stress ◽  
Insulin Receptors ◽  
Metabolic Dysfunction ◽  
Beneficial Effects ◽  
Glucose And Lipid Metabolism ◽  
Endocrine Hormone ◽  
Metabolic Conditions ◽  
The Brain

Neurodegenerative disorders are the most devastating disorder of the nervous system. The pathological basis of neurodegeneration is linked with dysfunctional protein trafficking, mitochondrial stress, environmental factors and aging. With the identification of insulin and insulin receptors in some parts of the brain, it has become evident that certain metabolic conditions associated with insulin dysfunction like Type 2 diabetes mellitus (T2DM), dyslipidemia, obesity etc., are also known to contribute to neurodegeneration mainly Alzheimer’s Disease (AD). Recently, a member of the fibroblast growth factor (FGF) superfamily, FGF21 has proved tremendous efficacy in diseases like diabetes mellitus, obesity and insulin resistance (IR). Increased levels of FGF21 have been reported to exert multiple beneficial effects in metabolic syndrome. FGF21 receptors are present in certain areas of the brain involved in learning and memory. However, despite extensive research, its function as a neuroprotectant in AD remains elusive. FGF21 is a circulating endocrine hormone which is mainly secreted by the liver primarily in fasting conditions. FGF21 exerts its effects after binding to FGFR1 and co-receptor, β-klotho (KLB). It is involved in regulating energy via glucose and lipid metabolism. It is believed that aberrant FGF21 signalling might account for various anomalies like neurodegeneration, cancer, metabolic dysfunction etc. Hence, this review will majorly focus on FGF21 role as a neuroprotectant and potential metabolic regulator. Moreover, we will also review its potential as an emerging candidate for combating metabolic stress induced neurodegenerative abnormalities.

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