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Bioactive Compounds for Brain Ischemia and Neurodegenerative Disease

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 21706

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Prof. Dr. Ramunė Morkūnienė

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1. Faculty of Pharmacy, Lithuanian University of Health Sciences, Kaunas, Lithuania
2. Neuroscience Institute, Lithuanian University of Health Sciences, Kaunas, Lithuania
Interests: cell death; energy metabolism; mitochondria; inflammation; neurodegenerative disorders; ischemia/reperfusion; amyloid proteins; brain cell cultures
Special Issues, Collections and Topics in MDPI journals

Dr. Dalia M. Kopustinskiene

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Faculty of Pharmacy, Lithuanian University of Health Sciences, Kaunas, Lithuania
Interests: protective and toxic mechanisms of bioactive compounds; ischemia; anoxia; stress conditions; cellular energy turnover; mitochondrial functions; ion channels; computer modeling in drug discovery
Special Issues, Collections and Topics in MDPI journals

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Dear Colleagues,

The world’s population is ageing. Ageing is the primary risk factor for most neurodegenerative diseases, including Alzheimers disease, Parkinson disease, Amyotrophic lateral sclerosis, etc. In addition, ageing is the strongest risk factor for ischemic stroke, and brain ischemia could progress and lead to the development of neurodegeneration. Both pathologies are life-threatening and may cause death or severe complications. Consequently, new therapies are constantly being sought and one of the research directions is a search for effective neuroprotective agents. Oxidative stress, mitochondrial injury, inflammation activation leading to brain cell death has been suggested as a key mechanisms of irreversible damage during many neurological disorders. The accumulation of several oxidation products in neurons during ageing and pathological conditions supports the idea that the presence of natural antioxidant biomolecules may be beneficial alternative therapy for the neurodegeneration and related diseases. Consequently, mitochondria-targeted or inflammatory response-regulated bioactive compounds may be promising candidate therapeutics for the prevention of brain cell death. We would like to invite you to submit original research papers or review articles to this Special Issue in “Bioactive Compounds for Brain Ischemia and Neurodegenerative Disease”, that would address any research topic highlighting recent identification of synthetic as well as natural-based bioactive molecules alleviating brain cell damages.

Prof. Dr. Ramunė Morkūnienė
Dr. Dalia M. Kopustinskiene
Guest Editors

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Keywords

brain
neuroprotection
neurodegenerative diseases
ischemia
mitochondria
oxidative stress
inflammation
bioactive compounds

Related Special Issue

Bioactive Compounds for Brain Ischemia and Neurodegenerative Disease—Second Edition in Molecules (1 article)

Published Papers (10 papers)

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Research

Jump to: Review

14 pages, 3034 KiB

Open AccessArticle

The Ameliorative Effect of Pioglitazone against Neuroinflammation Caused by Doxorubicin in Rats

by May M. Alsaud, Ahmad H. Alhowail, Maha A. Aldubayan and Ibtesam S. Almami

Molecules 2023, 28(12), 4775; https://doi.org/10.3390/molecules28124775 - 15 Jun 2023

Cited by 9 | Viewed by 1432

Abstract

Doxorubicin (DOX) is a chemotherapeutic agent that is linked with complications such as cardiotoxicity and cognitive dysfunction, known as chemobrain. Chemobrain affects up to 75% of cancer survivors, and there are no known therapeutic options for its treatment. This study aimed to determine the protective effect of pioglitazone (PIO) against DOX-induced cognitive impairment. Forty Wistar female rats were equally divided into four groups: control, DOX-treated, PIO-treated, and DOX + PIO-treated. DOX was administered at a dose of 5 mg/kg, i.p., twice a week for two weeks (cumulative dose, 20 mg/kg). PIO was dissolved in drinking water at a concentration of 2 mg/kg in the PIO and DOX-PIO groups. The survival rates, change in body weight, and behavioral assessment were performed using Y-maze, novel object recognition (NOR), and elevated plus maze (EPM), followed by estimation of neuroinflammatory cytokines IL-6, IL-1β, and TNF-α in brain homogenate and RT-PCR of a brain sample. Our results showed a survival rate of 40% and 65% in the DOX and DOX + PIO groups, respectively, compared with a 100% survival rate in the control and PIO treatment groups at the end of day 14. There was an insignificant increase in body weight in the PIO group and a significant reduction in the DOX and DOX + PIO groups as compared with the control groups. DOX-treated animals exhibited impairment of cognitive function, and the combination PIO showed reversal of DOX-induced cognitive impairment. This was evidenced by changes in IL-1β, TNF-α, and IL-6 levels and also by mRNA expression of TNF- α, and IL-6. In conclusion, PIO treatment produced a reversal of DOX-induced memory impairment by alleviating neuronal inflammation by modulating the expression of inflammatory cytokines. Full article

(This article belongs to the Special Issue Bioactive Compounds for Brain Ischemia and Neurodegenerative Disease)

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14 pages, 3029 KiB

Open AccessArticle

Drug Repurposing to Inhibit Histamine N-Methyl Transferase

by Elvia Mera Jiménez, Teresa Żołek, Paola Gabriela Hernández Perez, Rene Miranda Ruvalcaba, María Inés Nicolás-Vázquez and Maricarmen Hernández-Rodríguez

Molecules 2023, 28(2), 576; https://doi.org/10.3390/molecules28020576 - 06 Jan 2023

Cited by 4 | Viewed by 1686

Abstract

Lower activity of the histaminergic system is associated with neurological disorders, including Alzheimer’s disease (AD). Thus, the enhancement of histaminergic neurotransmission by inhibition of histamine N-methyl transferase (HNMT), which degrades histamine, appears as an important approach. For this purpose, rigid and flexible molecular docking studies of 185 FDA-approved drugs with the HNMT enzyme were carried out to select two compounds to perform molecular dynamics (MD) simulations to evaluate the binding free energies and stability of the enzyme–drug complexes. Finally, an HNMT inhibition assay was performed to corroborate their effect towards HNMT. Molecular docking studies with HNMT allowed the selection of dihydroergotamine and vilazodone since these molecules showed the lowest Gibbs free energy values. Analysis of the binding mode of vilazodone showed interactions with the binding pocket of HNMT with Glu28, Gln143, and Asn283. In contrast, dihydroergotamine binds to the HNMT active site in a different location, apparently because it is overall the more rigid ligand compared to flexible vilazodone. HNMT inhibitory activity for dihydroergotamine and vilazodone was corroborated (IC₅₀ = 72.89 μM and 45.01 μM, respectively) by in vitro assays. Drug repurposing of HNMT was achieved by employing computational studies. Full article

(This article belongs to the Special Issue Bioactive Compounds for Brain Ischemia and Neurodegenerative Disease)

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14 pages, 2437 KiB

Open AccessArticle

Tabersonine Inhibits the Lipopolysaccharide-Induced Neuroinflammatory Response in BV2 Microglia Cells via the NF-κB Signaling Pathway

by Jiaotai Shi, Chengbo Wang, Chunyan Sang, Stanislas Nsanzamahoro, Tian Chai, Jun Wang, Aimei Yang and Junli Yang

Molecules 2022, 27(21), 7521; https://doi.org/10.3390/molecules27217521 - 03 Nov 2022

Cited by 2 | Viewed by 1301

Abstract

The occurrence and development of neurodegenerative diseases is related to a variety of physiological and pathological changes. Neuroinflammation is one of the major factors that induces and aggravates neurodegenerative diseases. The most important manifestation of neuroinflammation is the activation of microglia. Therefore, inhibiting the abnormal activation of microglia is an important way to alleviate the occurrence of neuroinflammatory diseases. In this research, the inhibitory effect of tabersonine (Tab) on neuroinflammation was evaluated by establishing the BV2 neuroinflammation model induced by lipopolysaccharide (LPS). It was found that Tab significantly inhibited the production and expression of nitric oxide (NO), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and reactive oxygen species (ROS) in BV-2 cells stimulated by LPS. In addition, Tab can also inhibit the activation of nuclear factor-κB (NF-κB) induced by LPS, thus regulating inflammatory mediators such as inducible nitric oxide synthase (iNOS). These results indicated that Tab regulated the release of inflammatory mediators such as NO, IL-1β, TNF-α, and IL-6 by inhibiting NF-κB signaling pathway, and exerting its anti-neuroinflammatory effect. This is the first report regarding the inhibition on LPS-induced neuroinflammation in BV2 microglia cells of Tab, which indicated the drug development potential of Tab for the treatment of neurodegenerative diseases. Full article

(This article belongs to the Special Issue Bioactive Compounds for Brain Ischemia and Neurodegenerative Disease)

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13 pages, 2841 KiB

Open AccessArticle

Epidermal Growth Factor Receptor Kinase Inhibitor Ameliorates β-Amyloid Oligomer-Induced Alzheimer Disease in Swiss Albino Mice

by Jagadeesh Dhamodharan, Ganthimathy Sekhar and Arunachalam Muthuraman

Molecules 2022, 27(16), 5182; https://doi.org/10.3390/molecules27165182 - 14 Aug 2022

Cited by 4 | Viewed by 1695

Abstract

Alzheimer’s disease (AD) is one of the major neurodegenerative disorders, and its incidence increases globally every year. Currently, available AD drugs symptomatically treat AD with multiple adverse effects. Gefitinib (GE) is an epidermal growth factor receptor (EGFR) kinase inhibitor. EGFR is the preferred target for the treatment of AD, whereas the effect of GE in AD conditions is limited. The present study was designed to explore the ameliorative potential of GE in Aβ_1–42 oligomer-induced neurotoxicity in AD mice. AD was induced by intracerebroventricular (i.c.v.) injection of Aβ_1–42 oligomer (4 μg/4 μL) into the lateral ventricles of the mouse brain. The test compound, i.e., GE (2 and 4 mg/kg of body weight), was administered orally on days 10, 13, 16, 19, 22, 25, and 28, and the reference drug, i.e., donepezil (DP, 2 mg/kg), was administered orally from the 10th to 28th days. The behavioral changes were screened by the Morris water maze (MWM) test. Furthermore, biomarkers i.e., brain acetylcholinesterase (AChE), thiobarbituric acid reactive substances (TBARS), and reduced glutathione (GSH) levels were estimated from brain samples. The AD-associated histopathological changes were analyzed by hematoxylin and eosin staining. The administration of GE significantly ameliorated the AD-associated behavioral, biochemical, and histopathological changes. The ameliorative effect of GE against the Aβ_1–42 oligomer-associated neurotoxicity was due to its potent inhibition of EGFR kinase activation, as well as its antioxidant and antilipid peroxidative effect. Full article

(This article belongs to the Special Issue Bioactive Compounds for Brain Ischemia and Neurodegenerative Disease)

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9 pages, 2255 KiB

Open AccessArticle

A Small Natural Molecule S3 Protects Retinal Ganglion Cells and Promotes Parkin-Mediated Mitophagy against Excitotoxicity

by Dongli Zhuang, Rong Zhang, Haiyang Liu and Yi Dai

Molecules 2022, 27(15), 4957; https://doi.org/10.3390/molecules27154957 - 04 Aug 2022

Cited by 5 | Viewed by 1582

Abstract

Glutamate excitotoxicity may contribute to retinal ganglion cell (RGC) degeneration in glaucoma and other optic neuropathies, leading to irreversible blindness. Growing evidence has linked impaired mitochondrial quality control with RGCs degeneration, while parkin, an E3 ubiquitin ligase, has proved to be protective and promotes mitophagy in RGCs against excitotoxicity. The purpose of this study was to explore whether a small molecule S3 could modulate parkin-mediated mitophagy and has therapeutic potential for RGCs. The results showed that as an inhibitor of deubiquitinase USP30, S3 protected cultured RGCs and improved mitochondrial health against NMDA-induced excitotoxicity. Administration of S3 promoted the parkin expression and its downstream mitophagy-related proteins in RGCs. An upregulated ubiquitination level of Mfn2 and protein level of OPA1 were also observed in S3-treated RGCs, while parkin knockdown resulted in a major loss of the protective effect of S3 on RGCs under excitotoxicity. These findings demonstrated that S3 promoted RGC survival mainly through enhancing parkin-mediated mitophagy against excitotoxicity. The neuroprotective value of S3 in glaucoma and other optic neuropathies deserves further investigation. Full article

(This article belongs to the Special Issue Bioactive Compounds for Brain Ischemia and Neurodegenerative Disease)

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Review

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30 pages, 1602 KiB

Open AccessReview

Apitherapy in Post-Ischemic Brain Neurodegeneration of Alzheimer’s Disease Proteinopathy: Focus on Honey and Its Flavonoids and Phenolic Acids

by Ryszard Pluta, Barbara Miziak and Stanisław J. Czuczwar

Molecules 2023, 28(15), 5624; https://doi.org/10.3390/molecules28155624 - 25 Jul 2023

Cited by 2 | Viewed by 1908

Abstract

Neurodegeneration of the brain after ischemia is a major cause of severe, long-term disability, dementia, and mortality, which is a global problem. These phenomena are attributed to excitotoxicity, changes in the blood–brain barrier, neuroinflammation, oxidative stress, vasoconstriction, cerebral amyloid angiopathy, amyloid plaques, neurofibrillary tangles, and ultimately neuronal death. In addition, genetic factors such as post-ischemic changes in genetic programming in the expression of amyloid protein precursor, β-secretase, presenilin-1 and -2, and tau protein play an important role in the irreversible progression of post-ischemic neurodegeneration. Since current treatment is aimed at preventing symptoms such as dementia and disability, the search for causative therapy that would be helpful in preventing and treating post-ischemic neurodegeneration of Alzheimer’s disease proteinopathy is ongoing. Numerous studies have shown that the high contents of flavonoids and phenolic acids in honey have antioxidant, anti-inflammatory, anti-apoptotic, anti-amyloid, anti-tau protein, anticholinesterase, serotonergic, and AMPAK activities, influencing signal transmission and neuroprotective effects. Notably, in many preclinical studies, flavonoids and phenolic acids, the main components of honey, were also effective when administered after ischemia, suggesting their possible use in promoting recovery in stroke patients. This review provides new insight into honey’s potential to prevent brain ischemia as well as to ameliorate damage in advanced post-ischemic brain neurodegeneration. Full article

(This article belongs to the Special Issue Bioactive Compounds for Brain Ischemia and Neurodegenerative Disease)

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13 pages, 1390 KiB

Open AccessReview

Neuroprotective Effects of Carnosic Acid: Insight into Its Mechanisms of Action

by Fatima Javed Mirza, Saadia Zahid and R. M. Damian Holsinger

Molecules 2023, 28(5), 2306; https://doi.org/10.3390/molecules28052306 - 02 Mar 2023

Cited by 8 | Viewed by 2366

Abstract

Carnosic acid is a diterpenoid abundantly present in plants belonging to the genus Rosmarinus and Salvia of the family Lamiaceae, accounting for their application in traditional medicine. The diverse biological properties of carnosic acid that include antioxidant, anti-inflammatory, and anticarcinogenic activities have instigated studies on its mechanistic role, providing further insights into its potential as a therapeutic agent. Accumulating evidence has established the relevance of carnosic acid as a neuroprotective agent exhibiting therapeutic efficacy in combatting neuronal-injury-induced disorders. The physiological importance of carnosic acid in the mitigation of neurodegenerative disorders is just beginning to be understood. This review summarizes the current data on the mode of action through which carnosic acid exerts its neuroprotective role that may serve to strategize novel therapeutic approaches for these debilitating neurodegenerative disorders. Full article

(This article belongs to the Special Issue Bioactive Compounds for Brain Ischemia and Neurodegenerative Disease)

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22 pages, 601 KiB

Open AccessReview

Melatonin: A Potential Candidate for the Treatment of Experimental and Clinical Perinatal Asphyxia

by Ryszard Pluta, Wanda Furmaga-Jabłońska, Sławomir Januszewski and Agata Tarkowska

Molecules 2023, 28(3), 1105; https://doi.org/10.3390/molecules28031105 - 22 Jan 2023

Cited by 3 | Viewed by 2117

Abstract

Perinatal asphyxia is considered to be one of the major causes of brain neurodegeneration in full-term newborns. The worst consequence of perinatal asphyxia is neurodegenerative brain damage, also known as hypoxic-ischemic encephalopathy. Hypoxic-ischemic encephalopathy is the leading cause of mortality in term newborns. To date, due to the complex mechanisms of brain damage, no effective or causal treatment has been developed that would ensure complete neuroprotection. Although hypothermia is the standard of care for hypoxic-ischemic encephalopathy, it does not affect all changes associated with encephalopathy. Therefore, there is a need to develop effective treatment strategies, namely research into new agents and therapies. In recent years, it has been pointed out that natural compounds with neuroprotective properties, such as melatonin, can be used in the treatment of hypoxic-ischemic encephalopathy. This natural substance with anti-inflammatory, antioxidant, anti-apoptotic and neurofunctional properties has been shown to have pleiotropic prophylactic or therapeutic effects, mainly against experimental brain neurodegeneration in hypoxic-ischemic neonates. Melatonin is a natural neuroprotective hormone, which makes it promising for the treatment of neurodegeneration after asphyxia. It is supposed that melatonin alone or in combination with hypothermia may improve neurological outcomes in infants with hypoxic-ischemic encephalopathy. Melatonin has been shown to be effective in the last 20 years of research, mainly in animals with perinatal asphyxia but, so far, no clinical trials have been performed on a sufficient number of newborns. In this review, we summarize the advantages and limitations of melatonin research in the treatment of experimental and clinical perinatal asphyxia. Full article

(This article belongs to the Special Issue Bioactive Compounds for Brain Ischemia and Neurodegenerative Disease)

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16 pages, 1246 KiB

Open AccessReview

Cyclic Glycine-Proline (cGP) Normalises Insulin-Like Growth Factor-1 (IGF-1) Function: Clinical Significance in the Ageing Brain and in Age-Related Neurological Conditions

by Jian Guan, Fengxia Li, Dali Kang, Tim Anderson, Toni Pitcher, John Dalrymple-Alford, Paul Shorten and Gagandeep Singh-Mallah

Molecules 2023, 28(3), 1021; https://doi.org/10.3390/molecules28031021 - 19 Jan 2023

Cited by 1 | Viewed by 2986

Abstract

Insulin-like growth factor-1 (IGF-1) function declines with age and is associated with brain ageing and the progression of age-related neurological conditions. The reversible binding of IGF-1 to IGF binding protein (IGFBP)-3 regulates the amount of bioavailable, functional IGF-1 in circulation. Cyclic glycine-proline (cGP), a metabolite from the binding site of IGF-1, retains its affinity for IGFBP-3 and competes against IGF-1 for IGFBP-3 binding. Thus, cGP and IGFBP-3 collectively regulate the bioavailability of IGF-1. The molar ratio of cGP/IGF-1 represents the amount of bioavailable and functional IGF-1 in circulation. The cGP/IGF-1 molar ratio is low in patients with age-related conditions, including hypertension, stroke, and neurological disorders with cognitive impairment. Stroke patients with a higher cGP/IGF-1 molar ratio have more favourable clinical outcomes. The elderly with more cGP have better memory retention. An increase in the cGP/IGF-1 molar ratio with age is associated with normal cognition, whereas a decrease in this ratio with age is associated with dementia in Parkinson disease. In addition, cGP administration reduces systolic blood pressure, improves memory, and aids in stroke recovery. These clinical and experimental observations demonstrate the role of cGP in regulating IGF-1 function and its potential clinical applications in age-related brain diseases as a plasma biomarker for—and an intervention to improve—IGF-1 function. Full article

(This article belongs to the Special Issue Bioactive Compounds for Brain Ischemia and Neurodegenerative Disease)

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15 pages, 3235 KiB

Open AccessReview

BACE1 Inhibitors for Alzheimer’s Disease: The Past, Present and Any Future?

by Firas H. Bazzari and Amjad H. Bazzari

Molecules 2022, 27(24), 8823; https://doi.org/10.3390/molecules27248823 - 12 Dec 2022

Cited by 11 | Viewed by 3739

Abstract

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and the most common cause of dementia in the elderly. The complexity of AD has hindered the development of either a cure or a disease-modifying therapy to halt the disease progression. Numerous hypotheses were presented in order to explain the mechanisms underlying the pathogenesis of AD. Introduced in 1992, the “Amyloid Cascade Hypothesis” had a huge impact on the field and inspired the rise of various drug candidates, especially amyloid-beta (Aβ)-directed drugs; including beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors. Adopted by a number of pharmaceutical companies, the development of BACE1 inhibitors has gained momentum in the past decade with promising results from experimental and early clinical-phase studies. Nevertheless, nearly all BACE1 inhibitors failed in later phases of clinical trials, due to safety and/or efficacy issues, and others were discontinued early in favor of second-generation small-molecule candidates. This paper aims to provide a comprehensive review of all BACE1 inhibitors to ever reach clinical trials, and we discuss the challenges and different perspectives on whether BACE1 inhibitors are to be reconsidered or revitalized in the future. Full article

(This article belongs to the Special Issue Bioactive Compounds for Brain Ischemia and Neurodegenerative Disease)

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