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Neuroprotection by trans-resveratrol in rats with N-methyl-D-aspartate (NMDA)-induced retinal injury: Insights into the role of adenosine A1 receptors

Abd Ghapor AA, Abdul Nasir NA, Iezhitsa I, Agarwal R, Razali N

Neurosci Res, 2023 Aug;193:1-12.
PMID: 36796452 DOI: 10.1016/j.neures.2023.02.004

Adenosine A1 receptors (AA1R) have been shown to counteract N-methyl-D-aspartate (NMDA)-mediated glutamatergic excitotoxicity. In the present study, we investigated the role of AA1R in neuroprotection by trans-resveratrol (TR) against NMDA-induced retinal injury. In total, 48 rats were divided into the following four groups: normal rats pretreated with vehicle; rats that received NMDA (NMDA group); rats that received NMDA after pretreatment with TR; and rats that received NMDA after pretreatment with TR and 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), an AA1R antagonist. Assessment of general and visual behaviour was performed using the open field test and two-chamber mirror test, respectively, on Days 5 and 6 post NMDA injection. Seven days after NMDA injection, animals were euthanized, and eyeballs and optic nerves were harvested for histological parameters, whereas retinae were isolated to determine the redox status and expression of pro- and anti-apoptotic proteins. In the present study, the retinal and optic nerve morphology in the TR group was protected from NMDA-induced excitotoxic damage. These effects were correlated with the lower retinal expression of proapoptotic markers, lipid peroxidation, and markers of nitrosative/oxidative stress. The general and visual behavioural parameters in the TR group showed less anxiety-related behaviour and better visual function than those in the NMDA group. All the findings observed in the TR group were abolished by administration of DPCPX.

Matched MeSH terms: Neuroprotection
Phytochemicals from Calophyllum canum Hook f. ex T. Anderson and their neuroprotective effects

Lizazman MA, Jong VYM, Chua P, Lim WK, Karunakaran T

Nat Prod Res, 2023 Jun;37(12):2043-2048.
PMID: 35997666 DOI: 10.1080/14786419.2022.2116021

Previous phytochemical investigations reported that Calophyllum spp have biosynthesized a wide range of bioactive phenolics such as xanthones and coumarins. The phytochemical study conducted on the stem bark of C. canum has led to the isolation of eight trioxygenated xanthones namely: 5-methoxytrapezifolixanthone (1), 5-methoxyananixanthone (2), caloxanthone C (3), 1,5-dihydroxy-3-methoxy-4-isoprenylxanthone (4), 6-deoxyisojacareubin (5), euxanthone (6), trapezifolixanthone (7), ananixanthone (8), together with three common triterpenoids, β-sitosterol (9), friedelin (10), and stigmasterol (11). Furthermore, xanthones 1 and 2 were isolated for the first time as naturally occurring xanthones from the plant extract. The structures of these compounds were identified and elucidated using advanced spectroscopic techniques such as 1 D & 2 D NMR, MS, and FTIR. The neuroprotective property of selected compounds was tested through in vitro stroke model. Among all tested compounds, 1 µm of compounds 8, 9, and 10 showed significant neuroprotective activity via reduction of apoptosis by ∼ 50%.

Matched MeSH terms: Neuroprotection
Fulltext Antioxioxidant and antiapoptotic effects of Thymosin β4 in Aβ-induced SH-SY5Y cells via the 5-HTR1A/ERK axis

Zhang GH, Chin KL, Yan SY, Pare R

PLoS One, 2023;18(10):e0287817.
PMID: 37788276 DOI: 10.1371/journal.pone.0287817

Alzheimer's disease (AD) is a common amnestic cognitive impairment characterised by β-amyloid (Aβ) plaques deposit in the brain of the elderly. AD is a yet incurable disease due to its unknown exact pathogenesis and unavailability of effective remedies in clinical application. Thymosin β4 (Tβ4) is a housekeeping protein that plays important role in cell proliferation, migration and differentiation. It has the ability to protect and repair neurons however it is still unclear involvement in AD. Therefore, the aim of this study is to elucidate the role and mechanism of Tβ4 in mediating the improvement of AD. AD-like cell model was constructed in neuroblastoma cell line SH-SY5Y treated with Aβ. Overexpression of Tβ4 were done using lentivirus infection and downregulation through siRNA transfection. We performed western blot and flow cytometry to study the apoptosis and standard kits to measure the oxidative stress-associated biomarkers. There is significant increased in viability and decreased apoptosis in Tβ4 overexpression group compared to control. Furthermore, overexpression of Tβ4 suppressed the expression of pro-apoptotic markers such as Caspase-3, Caspase-8, and Bax meanwhile upregulated the expression of anti-apoptotic gene Bcl-2. Tβ4 alleviated oxidative damage by reducing MDA, LDH and ROS and increasing SOD and GSH-PX in Aβ-treated SH-SY5Y cells. We found that Tβ4 inhibit ERK/p38 MAPK pathway and intensify the expression of 5-HTR1A. Additionally, we showed that upregulation of 5-HTR1A dampened the Tβ4 to activate ERK signalling. In conclusion, our study revealed the neuroprotective role of Tβ4 in AD which may open up new therapeutic applications in AD treatment.

Matched MeSH terms: Neuroprotection
Fulltext The Monkey Head Mushroom and Memory Enhancement in Alzheimer's Disease

Yanshree, Yu WS, Fung ML, Lee CW, Lim LW, Wong KH

Cells, 2022 Jul 24;11(15).
PMID: 35892581 DOI: 10.3390/cells11152284

Alzheimer's disease (AD) is a neurodegenerative disorder, and no effective treatments are available to treat this disorder. Therefore, researchers have been investigating Hericium erinaceus, or the monkey head mushroom, an edible medicinal mushroom, as a possible treatment for AD. In this narrative review, we evaluated six preclinical and three clinical studies of the therapeutic effects of Hericium erinaceus on AD. Preclinical trials have successfully demonstrated that extracts and bioactive compounds of Hericium erinaceus have potential beneficial effects in ameliorating cognitive functioning and behavioral deficits in animal models of AD. A limited number of clinical studies have been conducted and several clinical trials are ongoing, which have thus far shown analogous outcomes to the preclinical studies. Nonetheless, future research on Hericium erinaceus needs to focus on elucidating the specific neuroprotective mechanisms and the target sites in AD. Additionally, standardized treatment parameters and universal regulatory systems need to be established to further ensure treatment safety and efficacy. In conclusion, Hericium erinaceus has therapeutic potential and may facilitate memory enhancement in patients with AD.

Matched MeSH terms: Neuroprotection/drug effects
LPS Preconditioning Attenuates Apoptosis Mechanism by Inhibiting NF-κB and Caspase-3 Activity: TLR4 Pre-activation in the Signaling Pathway of LPS-Induced Neuroprotection

Sangaran PG, Ibrahim ZA, Chik Z, Mohamed Z, Ahmadiani A

Mol Neurobiol, 2021 May;58(5):2407-2422.
PMID: 33421016 DOI: 10.1007/s12035-020-02227-3

Neuroinflammation, an inflammatory response within the nervous system, has been shown to be implicated in the progression of various neurodegenerative diseases. Recent in vivo studies showed that lipopolysaccharide (LPS) preconditioning provides neuroprotection by activating Toll-like receptor 4 (TLR4), one of the members for pattern recognition receptor (PRR) family that play critical role in host response to tissue injury, infection, and inflammation. Pre-exposure to low dose of LPS could confer a protective state against cellular apoptosis following subsequent stimulation with LPS at higher concentration, suggesting a role for TLR4 pre-activation in the signaling pathway of LPS-induced neuroprotection. However, the precise molecular mechanism associated with this protective effect is not well understood. In this article, we provide an overall review of the current state of our knowledge about LPS preconditioning in attenuating apoptosis mechanism and conferring neuroprotection via TLR4 signaling pathway.

Matched MeSH terms: Neuroprotection/drug effects*
Fulltext Essential Oils as a Potential Neuroprotective Remedy for Age-Related Neurodegenerative Diseases: A Review

Abd Rashed A, Abd Rahman AZ, Rathi DNG

Molecules, 2021 Feb 19;26(4).
PMID: 33669787 DOI: 10.3390/molecules26041107

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.

Matched MeSH terms: Neuroprotection*
Protective Effect of Natural Products against Huntington's Disease: An Overview of Scientific Evidence and Understanding Their Mechanism of Action

Lum PT, Sekar M, Gan SH, Bonam SR, Shaikh MF

ACS Chem Neurosci, 2021 Feb 03;12(3):391-418.
PMID: 33475334 DOI: 10.1021/acschemneuro.0c00824

Huntington's disease (HD), a neurodegenerative disease, normally starts in the prime of adult life, followed by a gradual occurrence of characteristic psychiatric disturbances and cognitive and motor dysfunction. To the best of our knowledge, there is no treatment available to completely mitigate the progression of HD. Among various therapeutic approaches, exhaustive literature reports have confirmed the medicinal benefits of natural products in HD experimental models. Building on this information, this review presents a brief overview of the neuroprotective mechanism(s) of natural products against in vitro/in vivo models of HD. Relevant studies were identified from several scientific databases, including PubMed, ScienceDirect, Scopus, and Google Scholar. After screening through literature from 2005 to the present, a total of 14 medicinal plant species and 30 naturally isolated compounds investigated against HD based on either in vitro or in vivo models were included in the present review. Behavioral outcomes in the HD in vivo model showed that natural compounds significantly attenuated 3-nitropropionic acid (3-NP) induced memory loss and motor incoordination. The biochemical alteration has been markedly alleviated with reduced lipid peroxidation, increased endogenous enzymatic antioxidants, reduced acetylcholinesterase activity, and increased mitochondrial energy production. Interestingly, following treatment with certain natural products, 3-NP-induced damage in the striatum was ameliorated, as seen histologically. Overall, natural products afforded varying degrees of neuroprotection in preclinical studies of HD via antioxidant and anti-inflammatory properties, preservation of mitochondrial function, inhibition of apoptosis, and induction of autophagy.

Matched MeSH terms: Neuroprotection
Improved spinal cord gray matter morphology induced by Spirulina platensis following spinal cord injury in rat models

Abdullahi D, Ahmad Annuar A, Sanusi J

Ultrastruct Pathol, 2020 Nov 20;44(4-6):359-371.
PMID: 32686973 DOI: 10.1080/01913123.2020.1792597

Despite intense preclinical research focusing on developing potential strategies of mitigating spinal cord injury (SCI), SCI still results in permanent, debilitating symptoms for which there are currently no effective pharmacological interventions to improve the recovery of the fine ultrastructure of the spinal cord. Spirulina platensis is thought to have potential neuroprotective effects. We have previously demonstrated its protective potential on the lesioned corticospinal tracts and behavioral recovery. In this study, spirulina, known for its neuroprotective properties was used to further explore its protective effects on spinal cord gray matter ultrastructural. Twenty-four Sprague-Dawley rats were used and divided into sham group (laminectomy without SCI), control group (SCI without S. platensis), and S. platensis group (SCI + 180 mg/kg S. platensis). All animals were anesthetized via intramuscular injection. A partial crush injury was induced at the level of T12. The rats were humanely sacrificed for 28 days postinjury for ultrastructural study. There were significant mean differences with respect to pairwise comparisons between the ultrastructural grading score of neuronal perikarya of control and the S. platensis following injury at day 28, which correlates with the functional locomotor recovery at this timepoint in our previous study. The group supplemented with spirulina, thus, revealed a better improvement in the fine ultrastructure of the spinal cord gray matter when compared to the control group thereby suggesting neuroprotective potentials of spirulina in mitigating the effects of spinal cord injury and inducing functional recovery.

Matched MeSH terms: Neuroprotection
Virgin Coconut Oil-Induced Neuroprotection in Lipopolysaccharide-Challenged Rats is Mediated, in Part, Through Cholinergic, Anti-Oxidative and Anti-Inflammatory Pathways

Rahim NS, Lim SM, Mani V, Hazalin NAMN, Majeed ABA, Ramasamy K

J Diet Suppl, 2020 Oct 14.
PMID: 33962540 DOI: 10.1080/19390211.2020.1830223

Neuroinflammation is associated with neuronal cell death and could lead to chronic neurodegeneration. This study investigated the neuroprotective potential of virgin coconut oil (VCO) against lipopolysaccharide (LPS)-induced cytotoxicity of neuroblastoma SK-N-SH cells. The findings were validated using Wistar rats, which were fed with 1-10 g/kg VCO for 31 days, exposed to LPS (0.25 mg/kg) and subjected to the Morris Water Maze Test. Brain homogenate was subjected to biochemical analyses and gene expression studies. α-Tocopherol (α-T; 150 mg/kg) served as the positive control. VCO (100 µg/mL) significantly (p

Matched MeSH terms: Neuroprotection
Fulltext From the Molecular Mechanism to Pre-clinical Results: Anti-epileptic Effects of Fingolimod

Paudel YN, Angelopoulou E, Piperi C, Gnatkovsky V, Othman I, Shaikh MF

Curr Neuropharmacol, 2020;18(11):1126-1137.
PMID: 32310049 DOI: 10.2174/1570159X18666200420125017

Epilepsy is a devastating neurological condition characterized by long-term tendency to generate unprovoked seizures, affecting around 1-2 % of the population worldwide. Epilepsy is a serious health concern which often associates with other neurobehavioral comorbidities that further worsen disease conditions. Despite tremendous research, the mainstream anti-epileptic drugs (AEDs) exert only symptomatic relief leading to 30% of untreatable patients. This reflects the complexity of the disease pathogenesis and urges the precise understanding of underlying mechanisms in order to explore novel therapeutic strategies that might alter the disease progression as well as minimize the epilepsy-associated comorbidities. Unfortunately, the development of novel AEDs might be a difficult process engaging huge funds, tremendous scientific efforts and stringent regulatory compliance with a possible chance of end-stage drug failure. Hence, an alternate strategy is drug repurposing, where anti-epileptic effects are elicited from drugs that are already used to treat non-epileptic disorders. Herein, we provide evidence of the anti-epileptic effects of Fingolimod (FTY720), a modulator of sphingosine-1-phosphate (S1P) receptor, USFDA approved already for Relapsing-Remitting Multiple Sclerosis (RRMS). Emerging experimental findings suggest that Fingolimod treatment exerts disease-modifying anti-epileptic effects based on its anti-neuroinflammatory properties, potent neuroprotection, anti-gliotic effects, myelin protection, reduction of mTOR signaling pathway and activation of microglia and astrocytes. We further discuss the underlying molecular crosstalk associated with the anti-epileptic effects of Fingolimod and provide evidence for repurposing Fingolimod to overcome the limitations of current AEDs.

Matched MeSH terms: Neuroprotection
miR-124 and Parkinson's disease: A biomarker with therapeutic potential

Angelopoulou E, Paudel YN, Piperi C

Pharmacol Res, 2019 12;150:104515.
PMID: 31707035 DOI: 10.1016/j.phrs.2019.104515

Parkinson's disease (PD) is a multifactorial disorder, attributed to a complex interplay between genetic and epigenetic factors. Although the exact etiology of the disease remains elusive, dysregulation of signaling pathways implicated in cell survival, apoptosis, protein aggregation, mitochondrial dysfunction, autophagy, oxidative damage and neuroinflammation, contributes to its pathogenesis. MicroRNAs (miRs) are endogenous short non-coding RNA molecules that negatively regulate gene expression at a post-transcriptional level. MiR-124 is one of the most abundantly expressed miRs in the brain that participates in neurogenesis, synapse morphology, neurotransmission, inflammation, autophagy and mitochondrial function. Accumulating pre-clinical evidence shows that miR-124 may act through calpain 1/p25/cyclin-dependent kinases 5 (CDK5), nuclear factor-kappa B (NF-κB), signal transducer and activator of transcription 3 (STAT3), Bcl-2-interacting mediator of cell death (Bim), 5' adenosine monophosphate-activated protein kinase (AMPK) and extracellular signal-regulated kinase (ERK)-mediated pathways to regulate cell survival, apoptosis, autophagy, mitochondrial dysfunction, oxidative damage and neuroinflammation in PD. Moreover, clinical evidence indicates that reduced plasma miR-124 levels may serve as a potential diagnostic biomarker in PD. This review provides an update of the pathogenic implication of miR-124 activity in PD and discusses its targeting potential for the development of future therapeutic strategies.

Matched MeSH terms: Neuroprotection
Current viral-mediated gene transfer research for treatment of Alzheimer's disease

Sasmita AO

Biotechnol Genet Eng Rev, 2019 Apr;35(1):26-45.
PMID: 30317930 DOI: 10.1080/02648725.2018.1523521

Alzheimer's disease (AD) is the most common form of dementia and has affected millions of individuals worldwide. The hallmarks of AD include the amyloid beta plaque deposits, tau neurofibrillary tangles, altered neuronal signaling, alongside decline in memory and cognitive functions. Conventional drug therapies do exist, such as donepezil or aducanumab, but these drugs mostly focus on halting AD progression instead of causing a reversal within the disease. In an effort to ameliorate and ultimately cure AD, researchers have delved into viral-mediated gene therapy to fix this disease from its root molecular causes. To date, adeno-associated virus and lentiviral vectors have remained the most vastly studied among other viral vectors to combat AD. These vectors could be employed alongside various genetic materials based on the types of processes we want to alter to yield a positive effect, such as disruption of amyloidogenic pathway, neuroprotection and lipid metabolism pathways. Recent studies and trials were reviewed in this article, highlighting their clinical significance, differences and limitations between each method. By learning from the different combinations and possibilities of viral-mediated gene transfer, researchers would then get a step closer in ameliorating symptoms and possibly in curing AD.

Matched MeSH terms: Neuroprotection
Fulltext Multi-targeting aurones with monoamine oxidase and amyloid-beta inhibitory activities: Structure-activity relationship and translating multi-potency to neuroprotection

Liew KF, Lee EH, Chan KL, Lee CY

Biomed Pharmacother, 2019 Feb;110:118-128.
PMID: 30466001 DOI: 10.1016/j.biopha.2018.11.054

Previously, a series of aurones bearing amine and carbamate functionalities was synthesized and evaluated for their cholinesterase inhibitory activity and drug-like attributes. In the present study, these aurones were evaluated for their multi-targeting properties in two Alzheimer's disease (AD)-related activities namely, monoamine oxidase (MAO) and amyloid-beta (Aβ) inhibition. Evaluation of the aurones for MAO inhibitory activity disclosed several potent selective inhibitors of MAO-B, particularly those with 6-methoxyl group attached at ring A. Of the different amine moieties attached as side chains, pyrrolidine-bearing aurones were prominent as represented by 2-2, the most potent inhibitor. Evaluation on the Aβ aggregation inhibition identified 4-3 as the best inhibitor with a percentage inhibition comparable to that of a known Aβ inhibitor curcumin. Examination on the neuroprotective ability of the more drug-like aurone 4-3 in two Caenorhabditis elegans neurodegeneration models showed 4-3 to protect the nematodes against both Aβ- and 6-hydroxydopamine-induced toxicities. These new activities further support 4-3 as a promising lead to develop the aurones as potential multipotent agents for neurodegenerative diseases.

Matched MeSH terms: Neuroprotection/drug effects*; Neuroprotection/physiology
The NLRP3 inflammasome is involved in the neuroprotective mechanism of neural stem cells against microglia-mediated toxicity in SH-SY5Y cells via the attenuation of tau hyperphosphorylation and amyloidogenesis

Chan EWL, Krishnansamy S, Wong C, Gan SY

Neurotoxicology, 2019 01;70:91-98.
PMID: 30408495 DOI: 10.1016/j.neuro.2018.11.001

The cognitive impairment caused by Alzheimer's disease (AD) is associated with beta-amyloid (Aβ) and tau proteins, and is accompanied by inflammation. Recently, a novel inflammasome signaling pathway has been uncovered. Inflammasomes are implicated in the execution of inflammatory responses and pyroptotic death leading to neurodegeneration. Thus, the inflammasome signaling pathway could be a potential therapeutic target for AD. Neural stem cells (NSCs) are multipotent cells that can self-renew and differentiate into distinct neural cells. NSC therapy has been considered to be a promising therapeutic approach in protecting the central nervous system and restoring it following damage. However, the mechanisms involved remain unclear. The aims of this study were to investigate the protective effects of NE4C neural stem cells against microglia-mediated neurotoxicity and to explore molecular mechanisms mediating their actions. NE4C decreased the levels of caspase-1 and IL-1β, and attenuated the level of the NLRP3 inflammasome and its associated protein adapter, apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) in LPS-stimulated BV2 microglial cells, possibly by regulating the phosphorylation of p38α MAPK. The conditioned media obtained from co-culture of LPS-stimulated BV2 and NE4C cells exhibited protective effects on SH-SY5Y cells against microglia-mediated neurotoxicity; this was associated with an attenuation of tau phosphorylation and amyloidogenesis and accompanied by down-regulation of GSK-3β and p38α MAPK signalling pathways. In conclusion, the present study suggested that NSC therapy could be a potential strategy against microglia-mediated neurotoxicity. NSCs regulate NLRP3 activation and IL-1β secretion, which are critical in the initiation of the inflammatory responses, hence preventing the release of neurotoxic pro-inflammatory factors by microglia. This eventually reduces tau hyperphosphylation and amyloidogenesis, possibly through the regulation of GSK-3β and p38α MAPK signalling pathways, and thus protects SH-SY5Y cells against microglia-mediated neurotoxicity.

Matched MeSH terms: Neuroprotection/drug effects; Neuroprotection/physiology*
Fulltext Human Embryonic Stem Cell-Derived Neural Lineages as In Vitro Models for Screening the Neuroprotective Properties of Lignosus rhinocerus (Cooke) Ryvarden

Yeo Y, Tan JBL, Lim LW, Tan KO, Heng BC, Lim WL

Biomed Res Int, 2019;2019:3126376.
PMID: 33204680 DOI: 10.1155/2019/3126376

In the biomedical field, there is growing interest in using human stem cell-derived neurons as in vitro models for pharmacological and toxicological screening of bioactive compounds extracted from natural products. Lignosus rhinocerus (Tiger Milk Mushroom) is used by indigenous communities in Malaysia as a traditional medicine to treat various diseases. The sclerotium of L. rhinocerus has been reported to have medicinal properties, including various bioactivities such as neuritogenic, anti-inflammatory, and anticancer effects. This study aims to investigate the neuroprotective activities of L. rhinocerus sclerotial extracts. Human embryonic stem cell (hESC)-derived neural lineages exposed to the synthetic glucocorticoid, dexamethasone (DEX), were used as the in vitro models. Excess glucocorticoids have been shown to adversely affect fetal brain development and impair differentiation of neural progenitor cells. Screening of different L. rhinocerus sclerotial extracts and DEX on the hESC-derived neural lineages was conducted using cell viability and neurite outgrowth assays. The neuroprotective effects of L. rhinocerus sclerotial extracts against DEX were further evaluated using apoptosis assays and Western blot analysis. Hot aqueous and methanol extracts of L. rhinocerus sclerotium promoted neurite outgrowth of hESC-derived neural stem cells (NSCs) with negligible cytotoxicity. Treatment with DEX decreased viability of NSCs by inducing apoptosis. Coincubation of L. rhinocerus methanol extract with DEX attenuated the DEX-induced apoptosis and reduction in phospho-Akt (pAkt) level in NSCs. These results suggest the involvement of Akt signaling in the neuroprotection of L. rhinocerus methanol extract against DEX-induced apoptosis in NSCs. Methanol extract of L. rhinocerus sclerotium exhibited potential neuroprotective activities against DEX-induced toxicity in hESC-derived NSCs. This study thus validates the use of human stem cell-derived neural lineages as potential in vitro models for screening of natural products with neuroprotective properties.

Matched MeSH terms: Neuroprotection*
Piper sarmentosum Roxb. Root Extracts Confer Neuroprotection by Attenuating Beta Amyloid-Induced Pro-Inflammatory Cytokines Released from Microglial Cells

Chan EWL, Yeo ETY, Wong KWL, See ML, Wong KY, Gan SY

Curr Alzheimer Res, 2019;16(3):251-260.
PMID: 30819080 DOI: 10.2174/1567205016666190228124630

BACKGROUND: Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder that eventually leads to severe cognitive impairment. Although the exact etiologies of AD still remain elusive, increasing evidence suggests that neuroinflammation cascades mediated by microglial cells are associated with AD. Piper sarmentosum Roxb. (PS) is a medicinal plant reported to possess various biological properties, including anti-inflammatory, anti-psychotic and anti-oxidant activity. However, little is known about the anti-inflammatory activity of PS roots despite their traditional use to treat inflammatory- mediated ailments.
OBJECTIVE: This study aimed to evaluate the anti-inflammatory and neuroprotective properties of extracts obtained from the roots of PS against beta-amyloid (Aβ)-induced microglial toxicity associated with the production of pro-inflammatory mediators.
METHOD: BV2 microglial cells were treated with hexane (RHXN), dichloromethane (RDCM), ethyl acetate (REA) and methanol (RMEOH) extracts of the roots of PS prior to activation by Aβ. The production and mRNA expression of pro-inflammatory mediators were evaluated by Griess reagent, ELISA kits and RT-qPCR respectively. The phosphorylation status of p38α MAPK was determined via western blot assay. BV2 conditioned medium was used to treat SH-SY5Y neuroblastoma cells and the neuroprotective effect was assessed using MTT assay.
RESULTS: PS root extracts, in particular RMEOH significantly attenuated the production and mRNA expression of IL-1β, IL-6 and TNF-α in Aβ-induced BV2 microglial cells. In addition, RHXN, REA and RMEOH extracts significantly reduced nitric oxide (NO) level and the inhibition of NO production was correlated with the total phenolic content of the extracts. Further mechanistic studies suggested that PS root extracts attenuated the production of cytokines by regulating the phosphorylation of p38α MAPK in microglia. Importantly, PS root extracts have protective effects against Aβ-induced indirect neurotoxicity either by inhibiting the production of NO, IL-1β, IL-6, and TNF-α in BV2 cells or by protecting SHSY5Y cells against these inflammatory mediators.
CONCLUSIONS: These findings provided evidence that PS root extracts confer neuroprotection against Aβ- induced microglial toxicity associated with the production of pro-inflammatory mediators and may be a potential therapeutic agent for inflammation-related neurological conditions including Alzheimer's disease (AD).

Matched MeSH terms: Neuroprotection/drug effects; Neuroprotection/physiology
Fulltext Embelin Protects Against Acute Pentylenetetrazole-Induced Seizures and Positively Modulates Cognitive Function in Adult Zebrafish

Kundap UP, Choo BKM, Kumari Y, Ahmed N, Othman IB, Shaikh MF

Front Pharmacol, 2019;10:1249.
PMID: 31708779 DOI: 10.3389/fphar.2019.01249

Purpose of the research: Epilepsy is a continuous process of neurodegeneration categorized by an enduring tendency to generate uncontrolled electrical firing known as seizures causing involuntary movement all over the body. Cognitive impairment and behavioral disturbances are among the more alarming co-morbidities of epilepsy. Anti-epileptic drugs (AEDs) were found to be successful in controlling epilepsy but are reported to worsen cognitive status in patients. Embelin (EMB) is a benzoquinone derived from the plant Embelia ribes and is reported to have central nervous system (CNS) activity. This study aims to evaluate the effectiveness of EMB against pentylenetetrazole (PTZ) induced acute seizures and its associated cognitive dysfunction. This was done via docking studies as well as evaluating neurotransmitter and gene expression in the zebrafish brain. The principal results: Behavioral observations showed that EMB reduced epileptic seizures and the T-maze study revealed that EMB improved the cognitive function of the fish. The docking study of EMB showed a higher affinity toward gamma-aminobutyric acid (GABAA) receptor as compared to the standard diazepam, raising the possibility of EMB working via the alpha subunit of the GABA receptor. EMB was found to modulate several genes, neurotransmitters, and also neuronal growth, all of which play an important role in improving cognitive status after epileptic seizures. Healthy zebrafish treated with EMB alone were found to have no behavioral and biochemical interference or side effects. The immunohistochemistry data suggested that EMB also promotes neuronal protection and neuronal migration in zebrafish brains. Major Conclusions: It was perceived that EMB suppresses seizure-like behavior via GABAA receptor pathway and has a positive impact on cognitive functions. The observed effect was supported by docking study, T-maze behavior, neurotransmitter and gene expression levels, and immunohistology study. The apparatus such as the T-maze and seizure scoring behavior tank were found to be a straightforward technique to score seizure and test learning ability after acute epileptic seizures. These research findings suggest that EMB could be a promising molecule for epilepsy induced learning and memory dysfunction.

Matched MeSH terms: Neuroprotection
C-Abl Inhibition; A Novel Therapeutic Target for Parkinson's Disease

Abushouk AI, Negida A, Elshenawy RA, Zein H, Hammad AM, Menshawy A, et al.

CNS Neurol Disord Drug Targets, 2018 Apr 26;17(1):14-21.
PMID: 28571531 DOI: 10.2174/1871527316666170602101538

Parkinson's disease (PD) is the most prevalent movement disorder in the world. The major pathological hallmarks of PD are death of dopaminergic neurons and the formation of Lewy bodies. At the moment, there is no cure for PD; current treatments are symptomatic. Investigators are searching for neuroprotective agents and disease modifying strategies to slow the progress of neurodegeneration. However, due to lack of data about the main pathological sequence of PD, many drug targets failed to provide neuroprotective effects in human trials. Recent evidence suggests the involvement of C-Abelson (c-Abl) tyrosine kinase enzyme in the pathogenesis of PD. Through parkin inactivation, alpha synuclein aggregation, and impaired autophagy of toxic elements. Experimental studies showed that (1) c-Abl activation is involved in neurodegeneration and (2) c-Abl inhibition shows neuroprotective effects and prevents dopaminergic neuronal' death. Current evidence from experimental studies and the first in-human trial shows that c-Abl inhibition holds the promise for neuroprotection against PD and therefore, justifies the movement towards larger clinical trials. In this review article, we discussed the role of c-Abl in PD pathogenesis and the findings of preclinical experiments and the first in-human trial. In addition, based on lessons from the last decade and current preclinical evidence, we provide recommendations for future research in this area.

Matched MeSH terms: Neuroprotection
Fulltext A brief review of potential neuroprotective roles of the culinary herb Ocimum basilicum

Manali Haniti, M.Z., Norazrina, A., Chan, K.M.

Medicine & Health, 2018;13(2):3-19.
MyJurnal

Neurodegenerative diseases commonly affect elderly population and are characterised by progressive neuronal loss. Oxidative stress is highly associated with neurodegeneration. The targeted herbal plant in this review, Ocimum basilicum (O. basilicum), is typically used in Indochina and Italian cuisine. Pharmacological studies on O. basilicum have demonstrated potent antioxidant activities with some reports of neuroprotective actions. This brief review highlights the potential neuroprotective roles of O. basilicum by discussing previously documented antioxidative actions of the plant extract, essential oils and its phytochemical compounds on the nervous system based on in vitro and in vivo studies. Accumulating evidence on the neuroprotective action of O. basilicum points to a notion that neuroprotection is made possible by way of its antioxidant properties and largely due to the presence of polyphenol compounds such as rosmarinic acid which has been identified as the major constituent. Although the mechanisms of O. basilicum antioxidant action have been proposed, further studies are required for better understanding of its antioxidant action leading to neuroprotective roles. It is also possible that the antioxidant actions of O. basilicum are mediated through synergism of a mixture of various naturally-occurring bioactive compounds in the plant, as is with many other plant-based food supplements, to produce the putative effects instead of a single bioactive compound from the plant. Therefore, specific targeting of neuroprotection by means of antioxidant actions warrants further preclinical and clinical studies investigating the therapeutic potentials of O. basilicum particularly in view of the prevention of neurodegenerative processes.

Matched MeSH terms: Neuroprotection
Fulltext Brain Lipopolysaccharide Preconditioning-Induced Gene Reprogramming Mediates a Tolerance State in Electroconvulsive Shock Model of Epilepsy

Amini E, Golpich M, Farjam AS, Kamalidehghan B, Mohamed Z, Ibrahim NM, et al.

Front Pharmacol, 2018;9:416.
PMID: 29765321 DOI: 10.3389/fphar.2018.00416

There is increasing evidence pointing toward the role of inflammatory processes in epileptic seizures, and reciprocally, prolonged seizures induce more inflammation in the brain. In this regard, effective strategies to control epilepsy resulting from neuroinflammation could be targeted. Based on the available data, preconditioning (PC) with low dose lipopolysaccharide (LPS) through the regulation of the TLR4 signaling pathway provides neuroprotection against subsequent challenge with injury in the brain. To test this, we examined the effects of a single and chronic brain LPS PC, which is expected to lead to reduction of inflammation against epileptic seizures induced by electroconvulsive shock (ECS). A total of 60 male Sprague Dawley rats were randomly assigned to five groups: control, vehicle (single and chronic), and LPS PC (single and chronic). We first recorded the data regarding the behavioral and histological changes. We further investigated the alterations of gene and protein expression of important mediators in relation to TLR4 and inflammatory signaling pathways. Interestingly, significant increased presence of NFκB inhibitors [Src homology 2-containing inositol phosphatase-1 (SHIP1) and Toll interacting protein (TOLLIP)] was observed in LPS-preconditioned animals. This result was also associated with over-expression of IRF3 activity and anti-inflammatory markers, along with down-regulation of pro-inflammatory mediators. Summarizing, the analysis revealed that PC with LPS prior to seizure induction may have a neuroprotective effect possibly by reprogramming the signaling response to injury.

Matched MeSH terms: Neuroprotection

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