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 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 Cyclo-oxygenase 2, a putative mediator of vessel remodeling, is expressed in the brain AVM vessels and associates with inflammation

2021 ◽  
Author(s):  
Sara Keränen ◽  
Santeri Suutarinen ◽  
Rahul Mallick ◽  
Johanna P. Laakkonen ◽  
Diana Guo ◽  
...  
Keyword(s):  
Quantitative Polymerase Chain Reaction ◽  
Rank Correlation ◽  
Inflammatory Cells ◽  
Vessel Remodeling ◽  
Brain Avm ◽  
Inflammatory Drugs ◽  
Polymerase Chain ◽  
The Brain ◽  
Cox2 Expression

Abstract Background Brain arteriovenous malformations (bAVM) may rupture causing disability or death. BAVM vessels are characterized by abnormally high flow that in general triggers expansive vessel remodeling mediated by cyclo-oxygenase-2 (COX2), the target of non-steroidal anti-inflammatory drugs. We investigated whether COX2 is expressed in bAVMs and whether it associates with inflammation and haemorrhage in these lesions. Methods Tissue was obtained from surgery of 139 bAVMs and 21 normal Circle of Willis samples. The samples were studied with immunohistochemistry and real-time quantitative polymerase chain reaction (RT-PCR). Clinical data was collected from patient records. Results COX2 expression was found in 78% (109/139) of the bAVMs and localized to the vessels’ lumen or medial layer in 70% (95/135) of the bAVMs. Receptors for prostaglandin E2, a COX2-derived mediator of vascular remodeling, were found in the endothelial and smooth muscle cells and perivascular inflammatory cells of bAVMs. COX2 was expressed by infiltrating inflammatory cells and correlated with the extent of inflammation (r = .231, p = .007, Spearman rank correlation). COX2 expression did not associate with haemorrhage. Conclusion COX2 is induced in bAVMs, and possibly participates in the regulation of vessel wall remodelling and ongoing inflammation. Role of COX2 signalling in the pathobiology and clinical course of bAVMs merits further studies.

scholarly journals Alzheimer’s Disease Pathogenesis: Role of Autophagy and Mitophagy Focusing in Microglia

2021 ◽  
Vol 22 (7) ◽  
pp. 3330
Author(s):  
Mehdi Eshraghi ◽  
Aida Adlimoghaddam ◽  
Amir Mahmoodzadeh ◽  
Farzaneh Sharifzad ◽  
Hamed Yasavoli-Sharahi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Target ◽  
Neurological Disorder ◽  
Inflammatory Cells ◽  
Disease Pathogenesis ◽  
Current Review ◽  
The Brain ◽  
Comprehensive Discussion

Alzheimer’s disease (AD) is a debilitating neurological disorder, and currently, there is no cure for it. Several pathologic alterations have been described in the brain of AD patients, but the ultimate causative mechanisms of AD are still elusive. The classic hallmarks of AD, including am-yloid plaques (Aβ) and tau tangles (tau), are the most studied features of AD. Unfortunately, all the efforts targeting these pathologies have failed to show the desired efficacy in AD patients so far. Neuroinflammation and impaired autophagy are two other main known pathologies in AD. It has been reported that these pathologies exist in AD brain long before the emergence of any clinical manifestation of AD. Microglia are the main inflammatory cells in the brain and are considered by many researchers as the next hope for finding a viable therapeutic target in AD. Interestingly, it appears that the autophagy and mitophagy are also changed in these cells in AD. Inside the cells, autophagy and inflammation interact in a bidirectional manner. In the current review, we briefly discussed an overview on autophagy and mitophagy in AD and then provided a comprehensive discussion on the role of these pathways in microglia and their involvement in AD pathogenesis.

scholarly journals Osteopontin Expression in the Brain Triggers Localized Inflammation and Cell Death When Immune Cells Are Activated by Pertussis Toxin

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Maria Cecilia Garibaldi Marcondes ◽  
Ryan Ojakian ◽  
Nikki Bortell ◽  
Claudia Flynn ◽  
Bruno Conti ◽  
...  
Keyword(s):  
Cell Death ◽  
Pertussis Toxin ◽  
Inflammatory Cells ◽  
Brain Inflammation ◽  
Molecular Pattern ◽  
Expression Site ◽  
Pattern Characteristic ◽  
Peripheral Cells ◽  
The Brain

Upregulation of osteopontin (OPN) is a characteristic of central nervous system pathologies. However, the role of OPN in inflammation is still controversial, since it can both prevent cell death and induce the migration of potentially damaging inflammatory cells. To understand the role of OPN in inflammation and cell survival, we expressed OPN, utilizing an adenoviral vector, in the caudoputamen of mice deficient in OPN, using beta-galactosidase- (β-gal-) expressing vector as control. The tissue pathology and the expression of proinflammatory genes were compared in both treatments. Interestingly, inflammatory infiltrate was only found when the OPN-vector was combined with a peripheral treatment with pertussis toxin (Ptx), which activated peripheral cells to express the OPN receptor CD44v6. Relative toβ-gal, OPN increased the levels of inflammatory markers, including IL13Rα1, CXCR3, and CD40L. In Ptx-treated OPN KOs, apoptotic TUNEL+ cells surrounding the OPN expression site increased, compared toβ-gal. Together, these results show that local OPN expression combined with a peripheral inflammatory stimulus, such as Ptx, may be implicated in the development of brain inflammation and induction of cell death, by driving a molecular pattern characteristic of cytotoxicity. These are characteristics of inflammatory pathologies of the CNS in which OPN upregulation is a hallmark.

Pathogenetic role of no-reflow phenomenon in experimental subarachnoid hemorrhage in dogs

1977 ◽  
Vol 46 (4) ◽  
pp. 454-466 ◽  
Author(s):  
Takao Asano ◽  
Keiji Sano
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Carbon Black ◽  
Acute Stage ◽  
Cerebrospinal Fluid Leakage ◽  
Pathogenetic Role ◽  
No Reflow ◽  
No Reflow Phenomenon ◽  
Sensory Evoked ◽  
The Brain

✓ The real pathogenetic role of no-reflow phenomenon in clinical situations such as the acute stage of subarachnoid hemorrhage (SAH) is not yet known. To study this problem, we carried out the following experiment in dogs: SAH was induced by withdrawing a needle previously inserted into the internal carotid artery through a small craniectomy in the lateral base of the skull. Complete dural repair and cranioplasty was done to avoid cerebrospinal fluid leakage. Cortical cerebral blood flow (CBF) changes, measured by a double-needle type thermocouple, intracranial pressure (ICP), electroencephalogram (EEG), and sensory evoked response were monitored under controlled ventilation for 3 hours after SAH. At the end of the experiment, the brain was perfused with carbon black solution at a pressure of 120 mm Hg. The 32 episodes of SAH thus induced yielded two basic patterns of ICP changes which simulated those previously reported with human SAH. In the first pattern, reactive hyperemia was always observed, followed by complete or incomplete recovery of cerebral function. Perfusion defects were frequently seen in the thalamus, basal ganglia, and parietooccipital cortex symmetrically. In the second pattern, prolonged elevation of ICP resulted in failure of recovery of both CBF and EEG. Carbon black filled only the pial arteries and the rest of the brain was totally unperfused. From the results, the pathogenetic role of the no-reflow phenomenon in the acute stage of SAH as influencing the prognosis is strongly suspected.

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 Dysfunction of the Glymphatic System as a Potential Mechanism of Perioperative Neurocognitive Disorders

2021 ◽  
Vol 13 ◽  
Author(s):  
Xuli Ren ◽  
Shan Liu ◽  
Chuang Lian ◽  
Haixia Li ◽  
Kai Li ◽  
...  
Keyword(s):  
Neurological Disorders ◽  
The Elderly ◽  
Brain Dysfunction ◽  
Neurocognitive Disorder ◽  
Potential Mechanism ◽  
Lymphatic Function ◽  
Cognitive Domains ◽  
Glymphatic System ◽  
The Brain

Perioperative neurocognitive disorder (PND) frequently occurs in the elderly as a severe postoperative complication and is characterized by a decline in cognitive function that impairs memory, attention, and other cognitive domains. Currently, the exact pathogenic mechanism of PND is multifaceted and remains unclear. The glymphatic system is a newly discovered glial-dependent perivascular network that subserves a pseudo-lymphatic function in the brain. Recent studies have highlighted the significant role of the glymphatic system in the removal of harmful metabolites in the brain. Dysfunction of the glymphatic system can reduce metabolic waste removal, leading to neuroinflammation and neurological disorders. We speculate that there is a causal relationship between the glymphatic system and symptomatic progression in PND. This paper reviews the current literature on the glymphatic system and some perioperative factors to discuss the role of the glymphatic system in PND.

scholarly journals Risk Factors and Pathogenesis of HIV-Associated Neurocognitive Disorder: The Role of Host Genetics

2018 ◽  
Vol 19 (11) ◽  
pp. 3594 ◽  
Author(s):  
Ian Olivier ◽  
Ramón Cacabelos ◽  
Vinogran Naidoo
Keyword(s):  
Risk Factors ◽  
Immune Response ◽  
Human Genetics ◽  
Hiv Treatment ◽  
Specific Gene ◽  
People Living With Hiv ◽  
Neurocognitive Disorder ◽  
Host Genetics ◽  
Hiv Associated Neurocognitive Disorder

Neurocognitive impairments associated with human immunodeficiency virus (HIV) infection remain a considerable health issue for almost half the people living with HIV, despite progress in HIV treatment through combination antiretroviral therapy (cART). The pathogenesis and risk factors of HIV-associated neurocognitive disorder (HAND) are still incompletely understood. This is partly due to the complexity of HAND diagnostics, as phenotypes present with high variability and change over time. Our current understanding is that HIV enters the central nervous system (CNS) during infection, persisting and replicating in resident immune and supporting cells, with the subsequent host immune response and inflammation likely adding to the development of HAND. Differences in host (human) genetics determine, in part, the effectiveness of the immune response and other factors that increase the vulnerability to HAND. This review describes findings from studies investigating the role of human host genetics in the pathogenesis of HAND, including potential risk factors for developing HAND. The similarities and differences between HAND and Alzheimer’s disease are also discussed. While some specific variations in host genes regulating immune responses and neurotransmission have been associated with protection or risk of HAND development, the effects are generally small and findings poorly replicated. Nevertheless, a few specific gene variants appear to affect the risk for developing HAND and aid our understanding of HAND pathogenesis.

scholarly journals Lead, Manganese, and Methylmercury as Risk Factors for Neurobehavioral Impairment in Advanced Age

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Bernard Weiss
Keyword(s):  
Risk Factors ◽  
Adverse Effects ◽  
Neurodegenerative Disease ◽  
Early Development ◽  
Neurodegenerative Disorders ◽  
Advanced Age ◽  
Metal Contaminants ◽  
Aging Populations ◽  
The Brain

Contamination of the environment by metals is recognized as a threat to health. One of their targets is the brain, and the adverse functional effects they induce are reflected by neurobehavioral assessments. Lead, manganese, and methylmercury are the metal contaminants linked most comprehensively to such disorders. Because many of these adverse effects can appear later in life, clues to the role of metals as risk factors for neurodegenerative disorders should be sought in the exposure histories of aging populations. A review of the available literature offers evidence that all three metals can produce, in advanced age, manifestations of neurobehavioral dysfunction associated with neurodegenerative disease. Among the critical unresolved questions is timing; that is, during which periods of the lifespan, including early development, do environmental exposures lay the foundations for their ultimate effects?

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