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Natural Bioactive Compounds against Neurodegenerative Diseases: Mechanistic Approach

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

Deadline for manuscript submissions: closed (28 February 2021) | Viewed by 23519

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Prof. Dr. Lucian Hritcu

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Faculty of Biology, Alexandru Ioan Cuza University of Iasi, Bd. Carol I, No. 11, 700506 Iasi, Romania
Interests: neurobiology; behavioral neuroscience; pharmacy; molecular biology
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Dear Colleagues,

Neurodegenerative diseases express a heterogeneous group of disorders characterized mainly by the degradation of memory and disorientation, which occurs with the loss of neuronal structure and function in different brain areas, including the hippocampus and neocortex. The selective elimination of axons, dendrites, and their branches; early vascular dysfunction; the aggregation and spread of misfolded proteins; and the activation of immune responses is a common scenario in neurodegeneration. Additionally, oxidative stress plays an essential role in the pathogenesis of many neurodegenerative diseases. Despite many pharmacotherapies involved in treating risk factors associated with neurodegenerative diseases, there is a great need to search for natural bioactive compounds that will be effective in brain disorders without affecting healthy cells. This Special Issue aims to identify and review natural bioactive compounds demonstrated to have a beneficial effect on neurodegenerative diseases and to elucidate their underlying mechanisms of action.

Prof. Dr. Lucian Hritcu
Guest Editor

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Keywords

natural bioactive compounds
oxidative stress
memory
anxiety
depression
protein aggregation
Alzheimer's Disease
Parkinson's Disease

Published Papers (7 papers)

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Research

13 pages, 2937 KiB

Open AccessArticle

Natural Alkaloid Compounds as Inhibitors for Alpha-Synuclein Seeded Fibril Formation and Toxicity

by Simona S. Ghanem, Hend S. Fayed, Qi Zhu, Jia-Hong Lu, Nishant N. Vaikath, Janarthanan Ponraj, Said Mansour and Omar M. A. El-Agnaf

Molecules 2021, 26(12), 3736; https://doi.org/10.3390/molecules26123736 - 19 Jun 2021

Cited by 19 | Viewed by 3628

Abstract

The accumulation and aggregation of α-synuclein (α-syn) is the main pathologic event in Parkinson’s disease (PD), dementia with Lewy bodies, and multiple system atrophy. α-Syn-seeded fibril formation and its induced toxicity occupy a major role in PD pathogenesis. Thus, assessing compounds that inhibit this seeding process is considered a key towards the therapeutics of synucleinopathies. Using biophysical and biochemical techniques and seeding-dependent cell viability assays, we screened a total of nine natural compounds of alkaloid origin extracted from Chinese medicinal herbs. Of these compounds, synephrine, trigonelline, cytisine, harmine, koumine, peimisine, and hupehenine exhibited in vitro inhibition of α-syn-seeded fibril formation. Furthermore, using cell viability assays, six of these compounds inhibited α-syn-seeding-dependent toxicity. These six potent inhibitors of amyloid fibril formation and toxicity caused by the seeding process represent a promising therapeutic strategy for the treatment of PD and other synucleinopathies. Full article

(This article belongs to the Special Issue Natural Bioactive Compounds against Neurodegenerative Diseases: Mechanistic Approach)

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18 pages, 3797 KiB

Open AccessArticle

Neuroprotective and Antioxidant Enhancing Properties of Selective Equisetum Extracts

by Denisa Batir-Marin, Monica Boev, Oana Cioanca, Cornelia Mircea, Ana Flavia Burlec, Galba Jean Beppe, Adrian Spac, Andreia Corciova, Lucian Hritcu and Monica Hancianu

Molecules 2021, 26(9), 2565; https://doi.org/10.3390/molecules26092565 - 28 Apr 2021

Cited by 9 | Viewed by 2681

Abstract

The sterile stems belonging to the Equisetum species are often used in traditional medicine of various nations, including Romanians. They are highly efficient in treating urinary tract infections, cardiovascular diseases, respiratory tract infections, and medical skin conditions due to their content of polyphenolic derivatives that have been isolated. In this regard, this study aimed to provide the chemical composition of the extracts obtained from the Equisetum species (E. pratense, E. sylvaticum, E. telmateia) and to investigate the biological action in vitro and in vivo. For the chemical characterization of the analyzed Equisetum species extracts, studies were performed by using ultra-high-performance liquid chromatography (UHPLC-DAD). In vitro evaluation of the antioxidant activity of the plant extracts obtained from these species of Equisetum genus was determined. The neuroprotective activity of these three ethanolic extracts from the Equisetum species using zebrafish tests was determined in vivo. All obtained results were statistically significant. The results indicate that E. sylvaticum extract has a significant antioxidant activity; whereas, E. pratense extract had anxiolytic and antidepressant effects significantly higher than the other two extracts used. All these determinations indicate promising results for the antioxidant in vitro tests and neuroprotective activity of in vivo tests, particularly mediated by their active principles. Full article

(This article belongs to the Special Issue Natural Bioactive Compounds against Neurodegenerative Diseases: Mechanistic Approach)

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15 pages, 2078 KiB

Open AccessArticle

6,7,4′-Trihydroxyflavanone Mitigates Methamphetamine-Induced Neurotoxicity in SH-SY5y Cells via Nrf2/heme Oxyganase-1 and PI3K/Akt/mTOR Signaling Pathways

by Hyun-Su Lee and Gil-Saeng Jeong

Molecules 2021, 26(9), 2442; https://doi.org/10.3390/molecules26092442 - 22 Apr 2021

Cited by 8 | Viewed by 1997

Abstract

Methamphetamine (METH) is a synthetic psychostimulant drug that has detrimental effects on the health of its users. Although it has been investigated as a cause of neurodegenerative disease due to its neurotoxicity, whether small molecules derived from natural products attenuate these side effects remains elusive. 6,7,4′-trihydroxyflavanone (THF) is a flavanone family that possesses various pharmacological activities, including anti-rheumatic, anti-ischemic, anti-inflammatory, anti-osteoclastogenic, and protective effects against METH-induced deactivation of T cells. However, little is known about whether THF protects neuronal cells from METH-induced neurotoxicity. Here, we investigated the protective effects of THF on neurotoxicity induced by METH exposure by enhancing the Nrf2/HO-1 and PI3K/Akt/mTOR signaling pathways in SH-SY5y cells. Treatment with THF did not lead to cytotoxicity, but attenuated METH-induced neurotoxicity by modulating the expression of apoptosis-related proteins, METH-induced oxidative stress, and PI3K/Akt/mTOR phosphorylation in METH-exposed SH-SY5y cells. Moreover, we found THF induced Nrf2 nuclear translocation and HO-1 expression. An inhibitor assay confirmed that the induction of HO-1 by THF attenuates METH-induced neurotoxicity. Therefore, we suggest that THF preserves neuronal cells from METH-induced neurotoxicity by upregulating HO-1 expression through the Nrf2 and PI3K/Akt/mTOR signaling pathways. Thus, THF has therapeutic potential for use in the treatment of METH-addicts suffering from neurodegenerative diseases. Full article

(This article belongs to the Special Issue Natural Bioactive Compounds against Neurodegenerative Diseases: Mechanistic Approach)

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16 pages, 6504 KiB

Open AccessArticle

Neuroprotective Effects of Baicalein, Wogonin, and Oroxylin A on Amyloid Beta-Induced Toxicity via NF-κB/MAPK Pathway Modulation

by Yeongseon Ji, Jin Han, Nayoung Lee, Jeong-Hyun Yoon, Kumju Youn, Hyun Joo Ha, Eunju Yoon, Dong Hyun Kim and Mira Jun

Molecules 2020, 25(21), 5087; https://doi.org/10.3390/molecules25215087 - 02 Nov 2020

Cited by 35 | Viewed by 3145

Abstract

Amyloid beta (Aβ) peptide, one of the most important pathogenic traits of Alzheimer’s disease (AD), invokes a cascade of oxidative damage and eventually leads to neuronal death. In the present study, baicalein, wogonin, and oroxylin A, main active flavones in Scutellaria baicalensis, were evaluated for their neuroprotective effects against Aβ_25–35-stimulated damage. All tested compounds decreased Aβ_25–35-induced ROS generation and cell cycle arrest. In particular, baicalein exhibited the strongest antioxidant activity. In addition, these compounds suppressed apoptosis by attenuating mitochondrial dysfunction such as loss of membrane potential, Ca²⁺ accumulation and Bax/Bcl-2 ratio. Furthermore, all tested flavones inhibited the expression of iNOS and COX-2, which resulted in suppressing inflammatory cytokines including TNF-α, NO, and PGE₂. Noticeably, all compounds exhibited the anti-inflammatory effects through downregulating NF-κB/MAPK pathway. Especially, oroxylin A was effective against both p65 and IκBα, while wogonin and baicalein were suppressed phospho-p65 and phospho-IκBα, respectively. Taken together, baicalein, wogonin, and oroxylin A can effectively relieve Aβ_25–35-stimulated neuronal apoptosis and inflammation in PC12 cells via downregulating NF-κB/MAPK signaling pathway. Full article

(This article belongs to the Special Issue Natural Bioactive Compounds against Neurodegenerative Diseases: Mechanistic Approach)

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27 pages, 5010 KiB

Open AccessArticle

Behavioral and Neurochemical Effects of Extra Virgin Olive Oil Total Phenolic Content and Sideritis Extract in Female Mice

by Nikolaos Kokras, Eleni Poulogiannopoulou, Marinos G. Sotiropoulos, Rafaella Paravatou, Eleni Goudani, Maria Dimitriadou, Electra Papakonstantinou, George Doxastakis, Despina N. Perrea, George Hloupis, Apostolis Angelis, Aikaterini Argyropoulou, Anthony Tsarbopoulos, Alexios-Leandros Skaltsounis and Christina Dalla

Molecules 2020, 25(21), 5000; https://doi.org/10.3390/molecules25215000 - 28 Oct 2020

Cited by 7 | Viewed by 2881

Abstract

The aim of this study was to determine the cognitive and behavioral effects of extra virgin olive oil total phenolic content (TPC) and Sideritis (SID) extracts in female mice, and identify the associated neurochemical changes in the hippocampus and the prefrontal cortex. All animals received intraperitoneal low or high doses of TPC, SID or vehicle treatment for 7 days and were subjected to the Open Field (OF), Novel Object Recognition (NOR) and Tail Suspension Test (TST). The prefrontal cortex and hippocampus were dissected for analysis of neurotransmitters and aminoacids with high performance liquid chromatography with electrochemical detection (HPLC-ED). Both TPC doses enhanced vertical activity and center entries in the OF, which could indicate an anxiolytic-like effect. In addition, TPC enhanced non-spatial working memory and, in high doses, exerted antidepressant effects. On the other hand, high SID doses remarkably decreased the animals’ overall activity. Locomotor and exploratory activities were closely associated with cortical increases in serotonin turnover induced by both treatments. Cognitive performance was linked to glutamate level changes. Furthermore, TPC reduced cortical taurine levels, while SID reduced cortical aspartate levels. TPC seems to have promising cognitive, anxiolytic and antidepressant effects, whereas SID has sedative effects in high doses. Both extracts act in the brain, but their specific actions and properties merit further exploration. Full article

(This article belongs to the Special Issue Natural Bioactive Compounds against Neurodegenerative Diseases: Mechanistic Approach)

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15 pages, 9593 KiB

Open AccessArticle

Propionic Acid and Fasudil as Treatment against Rotenone Toxicity in an In Vitro Model of Parkinson’s Disease

by Friederike Ostendorf, Judith Metzdorf, Ralf Gold, Aiden Haghikia and Lars Tönges

Molecules 2020, 25(11), 2502; https://doi.org/10.3390/molecules25112502 - 28 May 2020

Cited by 26 | Viewed by 4166

Abstract

Parkinson’s disease (PD) is a multifactorial neurodegenerative disease. In recent years, several studies demonstrated that the gastroenteric system and intestinal microbiome influence central nervous system function. The pathological mechanisms triggered thereby change neuronal function in neurodegenerative diseases including dopaminergic neurons in Parkinson´s disease. In this study, we employed a model system for PD of cultured primary mesencephalic cells and used the pesticide rotenone to model dopaminergic cell damage. We examined neuroprotective effects of the Rho kinase inhibitor Fasudil and the short chain fatty acid (SCFA) propionic acid on primary neurons in cell morphological assays, cell survival, gene and protein expression. Fasudil application resulted in significantly enhanced neuritic outgrowth and increased cell survival of dopaminergic cells. The application of propionic acid primarily promoted cell survival of dopaminergic cells against rotenone toxicity and increased neurite outgrowth to a moderate extent. Interestingly, Fasudil augmented gene expression of synaptophysin whereas gene expression levels of tyrosine hydroxylase (TH) were substantially increased by propionic acid. Concerning protein expression propionic acid treatment increased STAT3 levels but did not lead to an increased phosphorylation indicative of pathway activation. Our findings indicate that both Fasudil and propionic acid treatment show beneficial potential in rotenone-lesioned primary mesencephalic cells. Full article

(This article belongs to the Special Issue Natural Bioactive Compounds against Neurodegenerative Diseases: Mechanistic Approach)

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16 pages, 2414 KiB

Open AccessFeature PaperArticle

Cognitive Facilitation and Antioxidant Effects of an Essential Oil Mix on Scopolamine-Induced Amnesia in Rats: Molecular Modeling of In Vitro and In Vivo Approaches

by Razvan Stefan Boiangiu, Ion Brinza, Monica Hancianu, Ilkay Erdogan Orhan, Gokcen Eren, Elife Gündüz, Halis Ertas, Lucian Hritcu and Oana Cioanca

Molecules 2020, 25(7), 1519; https://doi.org/10.3390/molecules25071519 - 27 Mar 2020

Cited by 26 | Viewed by 4170

Abstract

The present study investigated the capability of an essential oil mix (MO: 1% and 3%) in ameliorating amnesia and brain oxidative stress in a rat model of scopolamine (Sco) and tried to explore the underlying mechanism. The MO was administered by inhalation to rats once daily for 21 days, while Sco (0.7 mg/kg) treatment was delivered 30 min before behavioral tests. Donepezil (DP: 5 mg/kg) was used as a positive reference drug. The cognitive-enhancing effects of the MO in the Sco rat model were assessed in the Y-maze, radial arm maze (RAM), and novel object recognition (NOR) tests. As identified by gas chromatography–mass spectrometry (GC–MS), the chemical composition of the MO is comprised by limonene (91.11%), followed by γ-terpinene (2.02%), β-myrcene (1.92%), β-pinene (1.76%), α-pinene (1.01%), sabinene (0.67%), linalool (0.55%), cymene (0.53%), and valencene (0.43%). Molecular interactions of limonene as the major compound in MO with the active site of butyrylcholinesterase (BChE) was explored via molecular docking experiments, and Van der Waals (vdW) contacts were observed between limonene and the active site residues SER198, HIS438, LEU286, VAL288, and PHE329. The brain oxidative status and acetylcholinesterase (AChE) and BChE inhibitory activities were also determined. MO reversed Sco-induced memory deficits and brain oxidative stress, along with cholinesterase inhibitory effects, which is an important mechanism in the anti-amnesia effect. Our present findings suggest that MO ameliorated memory impairment induced by Sco via restoration of the cholinergic system activity and brain antioxidant status. Full article

(This article belongs to the Special Issue Natural Bioactive Compounds against Neurodegenerative Diseases: Mechanistic Approach)

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