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1.
Uncoupling proteins as a therapeutic target for the development of new era drugs against neurodegenerative disorder.
Kumar, R, T, A, Singothu, S, Singh, SB, Bhandari, V
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2022;:112656
Abstract
Mitochondrial uncoupling proteins (UCP) are a part of the large family of mitochondrial solute carriers (SLC25s), concentrated in the inner mitochondrial membrane that carries protons from intermembrane space to the matrix. Further, some UCPs are also involved in the transportation of the fatty acid anions and catalyzed the proton transport by fatty acid cycling across the membrane. Out of the 5 UCPs, UCP 2, 4, and 5 are localized in the central nervous system (CNS), and alteration within the expression of these UCPs results in neuronal dysfunction and, ultimately, death of neurons. UCPs play a vital role in regulating mitochondrial membrane potential, preventing reactive oxygen species (ROS) production, alteration in neuronal activity, and the regulation of calcium homeostasis that ultimately results in the prevention of neuronal loss. These changes in mitochondria impact the function and survival of neurons playing a critical role in the progression of neurodegenerative diseases, particularly Alzheimer's disease (AD) and Parkinson's disease (PD). Additionally, UCP2 regulates the microglia response towards neuroinflammation by modulating microglia's M1 and M2 phenotypes. These microglia cells are further involved in regulating inflammatory response and synaptic functions. Moreover, UCP2, 4, and 5 are ubiquitously present in all brain regions that negatively regulate ROS production and inflammation, leading to the prevention of neuronal cell death. Increased ROS production is a common symptom reported in neurodegenerative diseases that affect several pathways concerned with neuronal death, either apoptosis or autophagy. These accumulating evidence suggested UCPs as a possible therapeutic target for the management of neurodegenerative diseases.
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Relationship between Diabetic Retinopathy and Systemic Neurodegenerative Diseases: A Systematic Review and Meta-analysis.
Pedersen, HE, Sandvik, CH, Subhi, Y, Grauslund, J, Pedersen, FN
Ophthalmology. Retina. 2022;(2):139-152
Abstract
TOPIC To examine the potential role of systemic neurodegeneration, this study aimed to provide an overview of the available evidence on the relationship between diabetic retinopathy (DR) and systemic neurodegeneration. CLINICAL RELEVANCE The association between DR and systemic neurodegeneration is inconsistent in the literature. A summary estimate on the measures of association is important to establish whether DR may be used as a risk marker of systemic neurodegeneration. METHODS We searched the literature databases PubMed/MEDLINE, EMBASE, and Cochrane Library on October 3, 2020, for all observational studies on humans evaluating the association between DR and systemic neurodegenerative diseases. Two authors conducted the literature search, study selection, and data extraction in an independent fashion. Studies were reviewed qualitatively in text and quantitatively in meta-analyses. Heterogeneity was evaluated with Cochran's Q and I2, and Funnel plot was used to investigate for skewed results and possible publication bias. RESULTS We identified 27 eligible studies with a total of 1 398 041 patients with diabetes. Diagnosis of DR was made using fundus photography or examination (n = 20), health registries (n = 4), was self-reported (n = 1), or was not disclosed in the remaining studies. Neurodegenerative conditions studied were cognitive impairment (n = 23), Alzheimer's disease (n = 3), and Parkinson's disease (n = 1). In cross-sectional and longitudinal studies, respectively, presence of any DR was associated with present (odds ratio [OR], 1.57; 95% confidence interval [CI], 1.02-2.43, P = 0.043) and incident (OR, 2.36; 95% CI, 1.50-3.71, P = 0.00021) systemic neurodegeneration, but severity of DR was not associated with differences in systemic neurodegeneration (OR, 0.98; 95% CI, 0.45-2.15, P = 0.96). CONCLUSIONS In this systematic review, DR appears to be a marker of systemic neurodegeneration. Further studies are warranted to better elucidate the clinical practical implications of this relationship.
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Methylxanthines Induce a Change in the AD/Neurodegeneration-Linked Lipid Profile in Neuroblastoma Cells.
Janitschke, D, Lauer, AA, Bachmann, CM, Winkler, J, Griebsch, LV, Pilz, SM, Theiss, EL, Grimm, HS, Hartmann, T, Grimm, MOW
International journal of molecular sciences. 2022;(4)
Abstract
Alzheimer's disease (AD) is characterized by an increased plaque burden and tangle accumulation in the brain accompanied by extensive lipid alterations. Methylxanthines (MTXs) are alkaloids frequently consumed by dietary intake known to interfere with the molecular mechanisms leading to AD. Besides the fact that MTX consumption is associated with changes in triglycerides and cholesterol in serum and liver, little is known about the effect of MTXs on other lipid classes, which raises the question of whether MTX can alter lipids in a way that may be relevant in AD. Here we have analyzed naturally occurring MTXs caffeine, theobromine, theophylline, and the synthetic MTXs pentoxifylline and propentofylline also used as drugs in different neuroblastoma cell lines. Our results show that lipid alterations are not limited to triglycerides and cholesterol in the liver and serum, but also include changes in sphingomyelins, ceramides, phosphatidylcholine, and plasmalogens in neuroblastoma cells. These changes comprise alterations known to be beneficial, but also adverse effects regarding AD were observed. Our results give an additional perspective of the complex link between MTX and AD, and suggest combining MTX with a lipid-altering diet compensating the adverse effects of MTX rather than using MTX alone to prevent or treat AD.
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4.
Sirtuins Modulation: A Promising Strategy for HIV-Associated Neurocognitive Impairments.
Figarola-Centurión, I, Escoto-Delgadillo, M, González-Enríquez, GV, Gutiérrez-Sevilla, JE, Vázquez-Valls, E, Torres-Mendoza, BM
International journal of molecular sciences. 2022;(2)
Abstract
HIV-Associated neurocognitive disorder (HAND) is one of the major concerns since it persists in 40% of this population. Nowadays, HAND neuropathogenesis is considered to be caused by the infected cells that cross the brain-blood barrier and produce viral proteins that can be secreted and internalized into neurons leading to disruption of cellular processes. The evidence points to viral proteins such as Tat as the causal agent for neuronal alteration and thus HAND. The hallmarks in Tat-induced neurodegeneration are endoplasmic reticulum stress and mitochondrial dysfunction. Sirtuins (SIRTs) are NAD+-dependent deacetylases involved in mitochondria biogenesis, unfolded protein response, and intrinsic apoptosis pathway. Tat interaction with these deacetylases causes inhibition of SIRT1 and SIRT3. Studies revealed that SIRTs activation promotes neuroprotection in neurodegenerative diseases such Alzheimer's and Parkinson's disease. Therefore, this review focuses on Tat-induced neurotoxicity mechanisms that involve SIRTs as key regulators and their modulation as a therapeutic strategy for tackling HAND and thereby improving the quality of life of people living with HIV.
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5.
NBIA Syndromes: A Step Forward from the Previous Knowledge.
Svetel, M, Dragašević, N, Petrović, I, Novaković, I, Tomić, A, Kresojević, N, Stanković, I, Kostić, V
Neurology India. 2021;(5):1380-1388
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Abstract
A disturbed iron metabolism may damage brain and trigger disorders known as neurodegeneration with brain iron accumulation (NBIA). NBIAs are rare, inherited disorders in which responsible mutations affect the function of proteins that participate in tissue iron homeostasis. Accumulated iron, which may be recognized as a low signal intensity on T2-weighted MRI images, oftentimes points to a diagnosis. Recent genetic discoveries confirm that NBIA is not a homogenous group of diseases. Fifteen different NBIAs have been described to date; among these, autosomal recessive inheritance was reported in 13, and autosmal dominant and X-linked dominant inheritance in one disease, respectively. Among NBIAs, the most common is pantothenate kinase-associated neurodegeneration (PKAN-NBIA 1) (30%-50% of all NBIA cases), that occurrs as a consequence of the autosomal recessive mutation in PANK2 gene, followed by phospholipase 2-associated neurodegeneration (PLAN, NBIA 2), due to mutation in PLA2G6 gene, and mitochondrial membrane protein-associated neurodegeneration (MPAN) with the underlying C19orf12 mutation [Table 1]. NBIAs are characterized by complex motor presentations from early-onset degeneration and premature fatality to adult-onset parkinsonism and dystonia. Epileptic seizures, pyramidal signs, visual disorders, and cognitive deterioration can develop. NBIAs are often refractory to therapeutical strategies, although certain interventions may provide significant symptomatic relief in selected patients. In this review, we discuss the expanding clinical spectrum of these complex and rare syndromes, their genetic and imaging features, and potential therapeutical targets and strategies.
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Essential Oils as a Potential Neuroprotective Remedy for Age-Related Neurodegenerative Diseases: A Review.
Abd Rashed, A, Abd Rahman, AZ, Rathi, DNG
Molecules (Basel, Switzerland). 2021;(4)
Abstract
Despite the improvements in life expectancy, neurodegenerative conditions have arguably become the most dreaded maladies of older people. The neuroprotective and anti-ageing potentials of essential oils (EOs) are widely evaluated around the globe. The objective of this review is to analyse the effectiveness of EOs as neuroprotective remedies among the four common age-related neurodegenerative diseases. The literature was extracted from three databases (PubMed, Web of Science and Google Scholar) between the years of 2010 to 2020 using the medical subject heading (MeSH) terms "essential oil", crossed with "Alzheimer's disease (AD)", "Huntington's disease (HD)", "Parkinson's disease (PD)" or "amyotrophic lateral sclerosis (ALS)". Eighty three percent (83%) of the studies were focused on AD, while another 12% focused on PD. No classifiable study was recorded on HD or ALS. EO from Salvia officinalis has been recorded as one of the most effective acetylcholinesterase and butyrylcholinesterase inhibitors. However, only Cinnamomum sp. has been assessed for its effectiveness in both AD and PD. Our review provided useful evidence on EOs as potential neuroprotective remedies for age-related neurodegenerative diseases.
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Miro (Mitochondrial Rho GTPase), a key player of mitochondrial axonal transport and mitochondrial dynamics in neurodegenerative diseases.
Panchal, K, Tiwari, AK
Mitochondrion. 2021;:118-135
Abstract
Miro (mitochondrial Rho GTPases) a mitochondrial outer membrane protein, plays a vital role in the microtubule-based mitochondrial axonal transport, mitochondrial dynamics (fusion and fission) and Mito-Ca2+ homeostasis. It forms a major protein complex with Milton (an adaptor protein), kinesin and dynein (motor proteins), and facilitates bidirectional mitochondrial axonal transport such as anterograde and retrograde transport. By forming this protein complex, Miro facilitates the mitochondrial axonal transport and fulfills the neuronal energy demand, maintain the mitochondrial homeostasis and neuronal survival. It has been demonstrated that altered mitochondrial biogenesis, improper mitochondrial axonal transport, and mitochondrial dynamics are the early pathologies associated with most of the neurodegenerative diseases (NDs). Being the sole mitochondrial outer membrane protein associated with mitochondrial axonal transport-related processes, Miro proteins can be one of the key players in various NDs such as Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). Thus, in the current review, we have discussed the evolutionarily conserved Miro proteins and its role in the pathogenesis of the various NDs. From this, we indicated that Miro proteins may act as a potential target for a novel therapeutic intervention for the treatment of various NDs.
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[Evaluation of the impact of lockdown on the health and lifestyle of users of the Fundacio Esclerosi Multiple's neurorehabilitation centres in Lleida and Reus].
Zabay-Neiro, MC, Nieves-Collado, M, Carrés-Gonzalez, G, Curto-Estupiñà, G, Gargallo-Noval, M, Martínez-Lerín, N, Torres-Calvo, S, Yaya-Tur, G
Revista de neurologia. 2021;(7):249-257
Abstract
INTRODUCTION On 13 March 2020, a state of alarm was declared due to the COVID-19 pandemic, resulting in total lockdown in Spain. The neurorehabilitation centres of the Fundacio Esclerosi Multiple (FEM) provide care for people diagnosed with neuroprogressive diseases with significant health deficits. We look at how lockdown can affect their way of life. AIMS To assess and manage the impact of lockdown on persons with multiple sclerosis (MS) and other neurodegenerative diseases. PATIENTS AND METHODS Analytical observational study. An anonymous questionnaire was administered to all the patients undergoing comprehensive rehabilitation treatment at two of the FEM centres; the survey included questions on the demographic and clinical characteristics of the subjects, and an assessment of the impact of the pandemic on the physical, social and psychological spheres. RESULTS A total of 202 surveys were analysed. The average age of the participants was 49.09 years and 77.8% had MS, while 22.2% had other conditions. The most frequently reported physical symptoms were muscle weakness, loss of balance and fatigue. The study population remained active during lockdown. More than half of them did not report any increase in cognitive symptoms, but they did mention an increased sense of worry on an emotional level. CONCLUSIONS We can state that the actions deployed by the FEM to reduce the consequences of lockdown have been effective and have minimised the occurrence of maladaptive behaviours. The study has also opened the door for us to add new lines of intervention.
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Targeted pharmacotherapy against neurodegeneration and neuroinflammation in early diabetic retinopathy.
Rolev, KD, Shu, XS, Ying, Y
Neuropharmacology. 2021;:108498
Abstract
Diabetic retinopathy (DR), the most frequent complication of diabetes, is one of the leading causes of irreversible blindness in working-age adults and has traditionally been regarded as a microvascular disease. However, increasing evidence has revealed that synaptic neurodegeneration of retinal ganglion cells (RGCs) and activation of glial cells may represent some of the earliest events in the pathogenesis of DR. Upon diabetes-induced metabolic stress, abnormal glycogen synthase kinase-3β (GSK-3β) activation drives tau hyperphosphorylation and β-catenin downregulation, leading to mitochondrial impairment and synaptic neurodegeneration prior to RGC apoptosis. Moreover, glial cell activation triggers enhanced inflammation and oxidative stress, which may accelerate the deterioration of diabetic RGCs neurodegeneration. These findings have opened up opportunities for therapies, such as inhibition of GSK-3β, glial cell activation, glutamate excitotoxicity and the use of neuroprotective drugs targeting early neurodegenerative processes in the retina and halting the progression of DR before the manifestation of microvascular abnormalities. Such interventions could potentially remedy early neurodegeneration and help prevent vision loss in people suffering from DR.
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Overview of Beneficial Effects of (Poly)phenol Metabolites in the Context of Neurodegenerative Diseases on Model Organisms.
Carregosa, D, Mota, S, Ferreira, S, Alves-Dias, B, Loncarevic-Vasiljkovic, N, Crespo, CL, Menezes, R, Teodoro, R, Santos, CND
Nutrients. 2021;(9)
Abstract
The rise of neurodegenerative diseases in an aging population is an increasing problem of health, social and economic consequences. Epidemiological and intervention studies have demonstrated that diets rich in (poly)phenols can have potent health benefits on cognitive decline and neurodegenerative diseases. Meanwhile, the role of gut microbiota is ever more evident in modulating the catabolism of (poly)phenols to dozens of low molecular weight (poly)phenol metabolites that have been identified in plasma and urine. These metabolites can reach circulation in higher concentrations than parent (poly)phenols and persist for longer periods of time. However, studies addressing their potential brain effects are still lacking. In this review, we will discuss different model organisms that have been used to study how low molecular weight (poly)phenol metabolites affect neuronal related mechanisms gathering critical insight on their potential to tackle the major hallmarks of neurodegeneration.