Role and Function of Dehydrogenases in CNS and Blood-Brain Barrier Pathophysiology

Naik, Pankaja; Prasad, Shikha; Cucullo, Luca

doi:10.5772/48338

Cited by 5 publications

(7 citation statements)

References 96 publications

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“…The theoretical energetic yield of the process from the complete oxidation of one glucose molecule to the end product generation of CO 2 and H 2 O is of 6X NADH, 2X FADH2, and 2X ATP (equivalent to 36X ATP molecules). The aerobic pathway also provides reducing equivalents (such as NADH and NADPH) to counteract oxidative stress caused by both endogenous and exogenous reactive oxidative species (ROS) [2,122,123]. …”

Section: Oxidative Stress At Bbb In Dmmentioning

confidence: 99%

“…During glycolysis itself, the intermediates formed can enter into different pathways of metabolism (Figure 3) - namely pentose phosphate pathway (PPP), hexosamine biosynthetic pathway (HBP), protein kinase C pathway (PKC) and AGE pathway. Glucose itself can also enter polyol pathway instead of glycolysis to form fructose [2,122,123]. We have subsequently discussed how these pathways abnormally get regulated in DM.…”

Section: Oxidative Stress At Bbb In Dmmentioning

confidence: 99%

See 1 more Smart Citation

Diabetes Mellitus and Blood-Brain Barrier Dysfunction: An Overview

Prasad

Sajja

Naik

et al. 2014

J Pharmacovigilance

151

106

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A host of diabetes-related insults to the central nervous system (CNS) have been clearly documented in type-1 and -2 diabetic patients as well as experimental animal models. These host of neurological disorders encompass hemodynamic impairments (e.g., stroke), vascular dementia, cognitive deficits (mild to moderate), as well as a number of neurochemical, electrophysiological and behavioral alterations. The underlying causes of diabetes-induced CNS complications are multifactorial and are relatively little understood although it is now evident that blood-brain barrier (BBB) damage plays a significant role in diabetes-dependent CNS disorders. Changes in plasma glucose levels (hyper- or hypoglycemia) have been associated with altered BBB transport functions (e.g., glucose, insulin, choline, amino acids, etc.), integrity (tight junction disruption), and oxidative stress in the CNS microcapillaries. Last two implicating a potential causal role for upregulation and activation of the receptor for advanced glycation end products (RAGE). This type I membrane-protein also transports amyloid-beta (Aβ) from the blood into the brain across the BBB thus, establishing a link between type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD, also referred to as “type 3 diabetes”). Hyperglycemia has been associated with progression of cerebral ischemia and the consequent enhancement of secondary brain injury. Difficulty in detecting vascular impairments in the large, heterogeneous brain microvascular bed and dissecting out the impact of hyper- and hypoglycemia in vivo has led to controversial results especially with regard to the effects of diabetes on BBB. In this article, we review the major findings and current knowledge with regard to the impact of diabetes on BBB integrity and function as well as specific brain microvascular effects of hyper- and hypoglycemia.

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Section: Oxidative Stress At Bbb In Dmmentioning

confidence: 99%

Section: Oxidative Stress At Bbb In Dmmentioning

confidence: 99%

Diabetes Mellitus and Blood-Brain Barrier Dysfunction: An Overview

Prasad

Sajja

Naik

et al. 2014

J Pharmacovigilance

151

106

View full text Add to dashboard Cite

show abstract

“…Oxidative glycolysis of one glucose molecule, with H 2 O and CO 2 as final products, can yield six NADH molecules, two FADH molecules and two ATP molecules, which is the equivalent of thirty-six ATP molecules. Aerobic glycolysis also provides the production of reducing equivalents, such as NADH and NADPH, which counteract oxidative stress caused by endogenous- and exogenous-reactive oxygen species (ROS) [ 78 , 79 , 80 ]. In normal conditions, the bioenergetic demand of mechanisms transporting various substances across the BBB is provided directly or indirectly by ATP.…”

Section: Blood–brain Barriermentioning

confidence: 99%

“…Each type of cell contains both sets of enzymes, and metabolites produced in the course of glycolysis may enter other metabolic pathways, such as the pentose phosphate pathway (PPP), hexosamine biosynthetic pathway (HBP), protein kinase C pathway (PKC) and AGE biosynthesis pathway. Glucose may also enter the polyol biosynthetic pathway, being finally isomerized to fructose [ 78 , 79 , 80 ].…”

Section: Blood–brain Barriermentioning

confidence: 99%

Effects of Diabetes Mellitus-Related Dysglycemia on the Functions of Blood–Brain Barrier and the Risk of Dementia

Wątroba

Grabowska

Szukiewicz

2023

IJMS

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Diabetes mellitus is one of the most common metabolic diseases worldwide, and its long-term complications include neuropathy, referring both to the peripheral and to the central nervous system. Detrimental effects of dysglycemia, especially hyperglycemia, on the structure and function of the blood–brain barrier (BBB), seem to be a significant backgrounds of diabetic neuropathy pertaining to the central nervous system (CNS). Effects of hyperglycemia, including excessive glucose influx to insulin-independent cells, may induce oxidative stress and secondary innate immunity dependent inflammatory response, which can damage cells within the CNS, thus promoting neurodegeneration and dementia. Advanced glycation end products (AGE) may exert similar, pro-inflammatory effects through activating receptors for advanced glycation end products (RAGE), as well as some pattern-recognition receptors (PRR). Moreover, long-term hyperglycemia can promote brain insulin resistance, which may in turn promote Aβ aggregate accumulation and tau hyperphosphorylation. This review is focused on a detailed analysis of the effects mentioned above towards the CNS, with special regard to mechanisms taking part in the pathogenesis of central long-term complications of diabetes mellitus initiated by the loss of BBB integrity.

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“…Although CPPs are promising vectors to deliver drugs across the BBB, no CPP-based treatment is currently used clinical practice, partly due to the lack of suitable preclinical models that can accurately mimic the features of BBB to discover potential CPPs in a high throughput way 114 . The widely used in vitro models for BBB are co-culturing of brain ECs (top), astrocytes and pericytes (bottom) in a transwell system [115][116][117] . Microfluidics could introduce blood flow to stimulate BBB more dynamically 118 .…”

Section: Cell-penetrating Peptidesmentioning

confidence: 99%

Integration of organoids in peptide drug discovery: rise of the high-throughput screening

Zhang

Shen

Wang

et al. 2023

Preprint

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Organoids are three-dimensional cell aggregates with near-physiologic cell behaviors and can undergo long-term expansion in vitro. They are amenable to high-throughput drug screening processes, which renders them a viable preclinical model for drug development. The procedure of organoid-based high-throughput screening has been extensively employed to discover small molecule drugs, encompassing the steps of generating organoids, examining efficient drugs in organoid cultures, and data assessment. Compared to small molecules, peptides are more straightforward to synthesize, can be modified chemically, and demonstrate a high degree of target specificity and low cytotoxicity. Therefore, they have emerged as promising carriers to deliver drugs to disease-associated targets, and could be efficient therapeutic drugs for various diseases. To date, organoids have been used to evaluate the efficacy of certain peptide agents; however, no organoid-based high-throughput screening of peptide drugs has been reported. Given the advantages of peptide drugs, there is an urgent need to establish organoid-based peptide high-throughput screening platforms. In this review, we discuss the typical approach of screening small-molecular drugs with the use of organoid cultures, as well as provide an overview of the studies that have incorporated organoids in peptide research. Drawing on the knowledge gained from small molecular screens, we explore the difficulties and potential avenues for creating new platforms to identify peptide agents using organoid models.

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Role and Function of Dehydrogenases in CNS and Blood-Brain Barrier Pathophysiology

Cited by 5 publications

References 96 publications

Diabetes Mellitus and Blood-Brain Barrier Dysfunction: An Overview

Diabetes Mellitus and Blood-Brain Barrier Dysfunction: An Overview

Effects of Diabetes Mellitus-Related Dysglycemia on the Functions of Blood–Brain Barrier and the Risk of Dementia

Integration of organoids in peptide drug discovery: rise of the high-throughput screening

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