scholarly journals 7,8-dihydroxyflavone Improves Neuropathological Changes in the Brain of Tg26 Mice, A Model for HIV-associated Neurocognitive Disorder

2020 ◽  
Author(s):  
Joseph Bryant ◽  
Sanketh Andhavarapu ◽  
Christopher Bever ◽  
Poornachander Guda ◽  
Akhil Katuri ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Brain Regions ◽  
Mitochondrial Damage ◽  
Data Sets ◽  
Neurocognitive Disorder ◽  
Hiv Patients ◽  
Neuroprotective Effects ◽  
Downstream Signaling ◽  
Hiv Associated Neurocognitive Disorder ◽  
The Brain

Abstract Background: The combined antiretroviral therapy (cART) era has significantly increased the lifespan of HIV patients, turning a fatal disease to a chronic one. However, this lower but persistent level of HIV infection increases the susceptibility of HIV-associated neurocognitive disorder (HAND). Therefore, research is currently seeking improved treatment for this complication of HIV. In HIV+ patients, low levels of brain derived neurotrophic factor (BDNF) has been associated with worse neurocognitive impairment. Hence, BDNF administration has been gaining relevance as a possible adjunct therapy for HAND. However, systemic administration of BDNF is impractical because of poor pharmacological profile.Methods: We investigated the neuroprotective effects of BDNF-mimicking 7,8 dihydroxyflavone (DHF), a bioactive high-affinity TrkB agonist, in the memory-involved hippocampus and brain cortex of Tg26 mice, a murine model for HAND. We immunohistochemically stained brain tissue sections from vehicle-treated wild type (WT), vehicle-treated Tg26, and DHF (5 mg/kg, i.p)-treated Tg26 mice to examine activation of TrkB and downstream signaling, expression of HIV-1 chemokine co-receptors CXCR4 and CCR5, neuroinflammation, and mitochondrial damage. A one-way ANOVA with a Bonferroni Comparison post-hoc test was performed to analyze the data sets. Results: In the brain regions of Tg26 mice, we observed astrogliosis, increased CXCR4 and CCR5 expression, neuroinflammation, and mitochondrial damage. Hippocampi and cortices of DHF treated mice exhibited a reversal of these pathological changes, suggesting the therapeutic potential of DHF in HAND. Our data indicates that DHF increases the phosphorylation of TrkB, providing new insights about the role of the TrkB-Akt-NFkB signaling pathway in mediating these pathological hallmarks.Conclusions: Our study provides an overview of how targeting BDNF-TrkB signaling in the pathophysiology of HAND may be relevant for future therapies, and sheds light on 7,8 Dihydroxyflavone as a potential adjunct therapeutic agent to current antiviral therapy.

scholarly journals 7,8-Dihydroxyflavone improves neuropathological changes in the brain of Tg26 mice, a model for HIV-associated neurocognitive disorder

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Joseph Bryant ◽  
Sanketh Andhavarapu ◽  
Christopher Bever ◽  
Poornachander Guda ◽  
Akhil Katuri ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Brain Regions ◽  
Future Research ◽  
Neurocognitive Disorder ◽  
Neuroprotective Effects ◽  
Antiviral Therapies ◽  
Combined Antiretroviral Therapy ◽  
Hiv Associated Neurocognitive Disorder ◽  
The Brain

AbstractThe combined antiretroviral therapy era has significantly increased the lifespan of people with HIV (PWH), turning a fatal disease to a chronic one. However, this lower but persistent level of HIV infection increases the susceptibility of HIV-associated neurocognitive disorder (HAND). Therefore, research is currently seeking improved treatment for this complication of HIV. In PWH, low levels of brain derived neurotrophic factor (BDNF) has been associated with worse neurocognitive impairment. Hence, BDNF administration has been gaining relevance as a possible adjunct therapy for HAND. However, systemic administration of BDNF is impractical because of poor pharmacological profile. Therefore, we investigated the neuroprotective effects of BDNF-mimicking 7,8 dihydroxyflavone (DHF), a bioactive high-affinity TrkB agonist, in the memory-involved hippocampus and brain cortex of Tg26 mice, a murine model for HAND. In these brain regions, we observed astrogliosis, increased expression of chemokine HIV-1 coreceptors CXCR4 and CCR5, neuroinflammation, and mitochondrial damage. Hippocampi and cortices of DHF treated mice exhibited a reversal of these pathological changes, suggesting the therapeutic potential of DHF in HAND. Moreover, our data indicates that DHF increases the phosphorylation of TrkB, providing new insights about the role of the TrkB–Akt–NFkB signaling pathway in mediating these pathological hallmarks. These findings guide future research as DHF shows promise as a TrkB agonist treatment for HAND patients in adjunction to the current antiviral therapies.

scholarly journals Tryptophan, Neurodegeneration and HIV-Associated Neurocognitive Disorder

2010 ◽  
Vol 3 ◽  
pp. IJTR.S4321 ◽  
Author(s):  
Nicholas W.S. Davies ◽  
Gilles Guillemin ◽  
Bruce J. Brew
Keyword(s):  
Neurodegenerative Disease ◽  
Differential Expression ◽  
Inflammatory Cells ◽  
Kynurenine Pathway ◽  
Motor Neurone ◽  
Neurocognitive Disorder ◽  
Pathogenetic Role ◽  
Hiv Associated Neurocognitive Disorder ◽  
The Brain

This review presents an up-to-date assessment of the role of the tryptophan metabolic and catabolic pathways in neurodegenerative disease and HIV-associated neurocognitive disorder. The kynurenine pathway and the effects of each of its enzymes and products are reviewed. The differential expression of the kynurenine pathway in cells within the brain, including inflammatory cells, is explored given the increasing recognition of the importance of inflammation in neurodegenerative disease. An overview of common mechanisms of neurodegeneration is presented before a review and discussion of the evidence for a pathogenetic role of the kynurenine pathway in Alzheimer's disease, HIV-associated neurocognitive disorder, Huntington's disease, motor neurone disease, and Parkinson's disease.

scholarly journals The Role of Urocortins in Intracerebral Hemorrhage

Biomolecules ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 96 ◽  
Author(s):  
Ker Woon Choy ◽  
Andy Po-Yi Tsai ◽  
Peter Bor-Chian Lin ◽  
Meng-Yu Wu ◽  
Chihyi Lee ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Brain Regions ◽  
Brain Parenchyma ◽  
Protective Mechanisms ◽  
Neuroprotective Effects ◽  
Blood Brain Barrier Disruption ◽  
Brain Barrier Disruption ◽  
G Protein Coupled ◽  
The Brain

Intracerebral hemorrhage (ICH) causes an accumulation of blood in the brain parenchyma that disrupts the normal neurological function of the brain. Despite extensive clinical trials, no medical or surgical therapy has shown to be effective in managing ICH, resulting in a poor prognosis for the patients. Urocortin (UCN) is a 40-amino-acid endogenous neuropeptide that belongs to the corticotropin-releasing hormone (CRH) family. The effect of UCN is activated by binding to two G-protein coupled receptors, CRH-R1 and CRH-R2, which are expressed in brain neurons and glial cells in various brain regions. Current research has shown that UCN exerts neuroprotective effects in ICH models via anti-inflammatory effects, which generally reduced brain edema and reduced blood-brain barrier disruption. These effects gradually help in the improvement of the neurological outcome, and thus, UCN may be a potential therapeutic target in the treatment of ICH. This review summarizes the data published to date on the role of UCN in ICH and the possible protective mechanisms underlined.

scholarly journals Neuroprotective Effects and Therapeutic Potential of Transcorneal Electrical Stimulation for Depression

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2492
Author(s):  
Wing-Shan Yu ◽  
So-Hyun Kwon ◽  
Stephen Kugbere Agadagba ◽  
Leanne-Lai-Hang Chan ◽  
Kah-Hui Wong ◽  
...  
Keyword(s):  
Electrical Stimulation ◽  
Therapeutic Potential ◽  
Brain Regions ◽  
Neuroprotective Effects ◽  
Transcorneal Electrical Stimulation ◽  
Beneficial Effects ◽  
Non Invasive ◽  
Antidepressant Treatments ◽  
Antidepressant Effects ◽  
Apoptosis And Inflammation

Transcorneal electrical stimulation (TES) has emerged as a non-invasive neuromodulation approach that exerts neuroprotection via diverse mechanisms, including neurotrophic, neuroplastic, anti-inflammatory, anti-apoptotic, anti-glutamatergic, and vasodilation mechanisms. Although current studies of TES have mainly focused on its applications in ophthalmology, several lines of evidence point towards its putative use in treating depression. Apart from stimulating visual-related structures and promoting visual restoration, TES has also been shown to activate brain regions that are involved in mood alterations and can induce antidepressant-like behaviour in animals. The beneficial effects of TES in depression were further supported by its shared mechanisms with FDA-approved antidepressant treatments, including its neuroprotective properties against apoptosis and inflammation, and its ability to enhance the neurotrophic expression. This article critically reviews the current findings on the neuroprotective effects of TES and provides evidence to support our hypothesis that TES possesses antidepressant effects.

scholarly journals Therapeutic Hypothermia Achieves Neuroprotection via a Decrease in Acetylcholine with a Concurrent Increase in Carnitine in the Neonatal Hypoxia-Ischemia

2015 ◽  
Vol 35 (5) ◽  
pp. 794-805 ◽  
Author(s):  
Toshiki Takenouchi ◽  
Yuki Sugiura ◽  
Takayuki Morikawa ◽  
Tsuyoshi Nakanishi ◽  
Yoshiko Nagahata ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Therapeutic Hypothermia ◽  
Quantitative Imaging ◽  
Imaging Mass Spectrometry ◽  
Brain Regions ◽  
Acetyl Coa ◽  
Neuroprotective Effects ◽  
Neurologic Outcomes ◽  
Hypoxia Ischemia ◽  
The Brain

Although therapeutic hypothermia is known to improve neurologic outcomes after perinatal cerebral hypoxia-ischemia, etiology remains unknown. To decipher the mechanisms whereby hypothermia regulates metabolic dynamics in different brain regions, we used a two-step approach: a metabolomics to target metabolic pathways responding to cooling, and a quantitative imaging mass spectrometry to reveal spatial alterations in targeted metabolites in the brain. Seven-day postnatal rats underwent the permanent ligation of the left common carotid artery followed by exposure to 8% O2 for 2.5 hours. The pups were returned to normoxic conditions at either 38°C or 30°C for 3 hours. The brain metabolic states were rapidly fixed using in situ freezing. The profiling of 107 metabolites showed that hypothermia diminishes the carbon biomass related to acetyl moieties, such as pyruvate and acetyl-CoA; conversely, it increases deacetylated metabolites, such as carnitine and choline. Quantitative imaging mass spectrometry demarcated that hypothermia diminishes the acetylcholine contents specifically in hippocampus and amygdala. Such decreases were associated with an inverse increase in carnitine in the same anatomic regions. These findings imply that hypothermia achieves its neuroprotective effects by mediating the cellular acetylation status through a coordinated suppression of acetyl-CoA, which resides in metabolic junctions of glycolysis, amino-acid catabolism, and ketolysis.

scholarly journals An Immunological Approach to Increase the Brain’s Resilience to Insults

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
En-Ju D. Lin ◽  
C. Wymond Symes ◽  
Andrea Townsend-Nicholson ◽  
Matthias Klugmann ◽  
Claudia B. Klugmann ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Recombinant Proteins ◽  
Therapeutic Potential ◽  
Humoral Response ◽  
Scaffolding Protein ◽  
Genetic Approach ◽  
Neuroprotective Effects ◽  
Immunological Approach ◽  
Antibody Titers ◽  
The Brain

We have previously demonstrated the therapeutic potential of inducing a humoral response with autoantibodies to the N-methyl D-aspartate (NMDA) receptor using a genetic approach. In this study, we generated three recombinant proteins to different functional domains of the NMDA receptor, which is implicated in mediating brain tolerance, specifically NR1[21–375], NR1[313–619], NR1[654–800], and an intracellular scaffolding protein, Homer1a, with a similar anatomical expression pattern. All peptides showed similar antigenicity and antibody titers following systemic vaccination, and all animals thrived. Two months following vaccination, rats were administered the potent neurotoxin, kainic acid. NR1[21–375] animals showed an antiepileptic phenotype but no neuroprotection. Remarkably, despite ineffective antiepileptic activity, 6 of 7 seizing NR1[654–800] rats showed absolutely no injury with only minimal changes in the remaining animal, whereas the majority of persistently seizing rats in the other groups showed moderate to severe hippocampal injury. CREB, BDNF, and HSP70, proteins associated with preconditioning, were selectively upregulated in the hippocampus of NR1[654–800] animals, consistent with the observed neuroprotective phenotype. These results identify NR1 epitopes important in conferring anticonvulsive and neuroprotective effects and support the concept of an immunological strategy to induce a chronic state of tolerance in the brain.

scholarly journals Neuroprotective Effect of Dexmedetomidine on Hyperoxia-Induced Toxicity in the Neonatal Rat Brain

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Marco Sifringer ◽  
Clarissa von Haefen ◽  
Maria Krain ◽  
Nadine Paeschke ◽  
Ivo Bendix ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Brain Injury ◽  
Rat Brain ◽  
Therapeutic Potential ◽  
Neuroprotective Effect ◽  
Brain Regions ◽  
Neonatal Rat ◽  
Neuroprotective Effects ◽  
Stress Markers ◽  
Oxygen Administration

Dexmedetomidine is a highly selective agonist ofα2-receptors with sedative, anxiolytic, analgesic, and anesthetic properties. Neuroprotective effects of dexmedetomidine have been reported in various brain injury models. In the present study, we investigated the effects of dexmedetomidine on neurodegeneration, oxidative stress markers, and inflammation following the induction of hyperoxia in neonatal rats. Six-day-old Wistar rats received different concentrations of dexmedetomidine (1, 5, or 10 µg/kg bodyweight) and were exposed to 80% oxygen for 24 h. Sex-matched littermates kept in room air and injected with normal saline or dexmedetomidine served as controls. Dexmedetomidine pretreatment significantly reduced hyperoxia-induced neurodegeneration in different brain regions of the neonatal rat. In addition, dexmedetomidine restored the reduced/oxidized glutathione ratio and attenuated the levels of malondialdehyde, a marker of lipid peroxidation, after exposure to high oxygen concentration. Moreover, administration of dexmedetomidine induced downregulation of IL-1βon mRNA and protein level in the developing rat brain. Dexmedetomidine provides protections against toxic oxygen induced neonatal brain injury which is likely associated with oxidative stress signaling and inflammatory cytokines. Our results suggest that dexmedetomidine may have a therapeutic potential since oxygen administration to neonates is sometimes inevitable.

scholarly journals There is no single functional atlas even for a single individual: Parcellation of the human brain is state dependent

2018 ◽  
Author(s):  
Mehraveh Salehi ◽  
Abigail S. Greene ◽  
Amin Karbasi ◽  
Xilin Shen ◽  
Dustin Scheinost ◽  
...  
Keyword(s):  
Human Brain ◽  
Brain Regions ◽  
Fmri Data ◽  
Brain State ◽  
Data Sets ◽  
Single Individual ◽  
Underlying Assumption ◽  
State Dependent ◽  
Independent Replication ◽  
The Brain

AbstractThe goal of human brain mapping has long been to delineate the functional subunits in the brain and elucidate the functional role of each of these brain regions. Recent work has focused on whole-brain parcellation of functional Magnetic Resonance Imaging (fMRI) data to identify these subunits and create a functional atlas. Functional connectivity approaches to understand the brain at the network level require such an atlas to assess connections between parcels and extract network properties. While no single functional atlas has emerged as the dominant atlas to date, there remains an underlying assumption that such an atlas exists. Using fMRI data from a highly sampled subject as well as two independent replication data sets, we demonstrate that functional parcellations based on fMRI connectivity data reconfigure substantially and in a meaningful manner, according to brain state.

scholarly journals L-Serine, an Endogenous Amino Acid, Is a Potential Neuroprotective Agent for Neurological Disease and Injury

2021 ◽  
Vol 14 ◽  
Author(s):  
Lisha Ye ◽  
Yechao Sun ◽  
Zhenglin Jiang ◽  
Guohua Wang
Keyword(s):  
Amino Acid ◽  
Neuronal Development ◽  
Therapeutic Potential ◽  
Neurological Diseases ◽  
Neurological Injury ◽  
Therapeutic Effects ◽  
Cns Injury ◽  
Neuroprotective Effects ◽  
Neuroprotective Agent ◽  
The Brain

Central nervous system (CNS) lesions are major causes of human death and disability worldwide, and they cause different extents of motor and sensory dysfunction in patients. Thus, it is crucial to develop new effective neuroprotective drugs and approaches targeted to the heterogeneous nature of CNS injury and disease. L-serine is an indispensable neurotrophic factor and a precursor for neurotransmitters. Although L-serine is a native amino acid supplement, its metabolic products have been shown to be essential not only for cell proliferation but also for neuronal development and specific functions in the brain. Growing evidence has suggested that L-serine regulates the release of several cytokines in the brain under some neuropathological conditions to recover cognitive function, improve cerebral blood flow, inhibit inflammation, promote remyelination and exert other neuroprotective effects on neurological injury. L-serine has also been used to treat epilepsy, schizophrenia, psychosis, and Alzheimer’s Disease as well as other neurological diseases. Furthermore, the dosing of animals with L-serine and human clinical trials investigating the therapeutic effects of L-serine generally support the safety of L-serine. The high significance of this review lies in its emphasis on the therapeutic potential of using L-serine as a general treatment for numerous CNS diseases and injuries. Because L-serine performs a broad spectrum of functions, it may be clinically used as an effective neuroprotective agent.

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