Neuroprotective Evaluation of N-Benzyl-2-[4-(Aryl)-1H-1,2, 3-Triazol-1-Yl]ethan-1-Imine Oxides

In Part I of this report, the authors reviewed preclinical and clinical evidence of neuroprotection by psychotropics and proposed criteria to predict translational neuroprotection. Here, the authors review a broad array of neuroprotective mechanisms and, based on evidence reviewed in Part I, consider agents with pharmacodynamic mechanisms of action that may be associated with neuroprotection. The neuroprotective potential of the pharmacodynamic mechanisms discussed here are held in common with drugs that evidenced neuroprotective potential in Part I. The agents examined here have symptomatic utility in neurodegenerative disease neuropsychiatric disorders and combine the most promising pharmacodynamic mechanisms yet have received insufficient research to date. Modafinil, duloxetine, ziprasidone, s-zopiclone, and ramelteon are evaluated in terms of their putative neuropsychiatric symptomatic and heuristic neuroprotective disease-modifying potentials. The authors review these agents in terms of their potential for clinical neuroprotection and suggest a criterion-based research agenda for future studies of their neuroprotective potential. Further research is needed with regard to the 10 translational neuroprotective candidate criteria, neuroprotective clinical trials, the correlation of psychotropic pharmacodynamic mechanisms with neuroprotective actions, and the translational predictive utility of the proposed candidate criteria.

Psychopharmacological Neuroprotection in Neurodegenerative Disease: Assessing the Preclinical Data

This manuscript reviews the preclinical in vitro, ex vivo, and nonhuman in vivo effects of psychopharmacological agents in clinical use on cell physiology with a view toward identifying agents with neuroprotective properties in neurodegenerative disease. These agents are routinely used in the symptomatic treatment of neurodegenerative disease. Each agent is reviewed in terms of its effects on pathogenic proteins, proteasomal function, mitochondrial viability, mitochondrial function and metabolism, mitochondrial permeability transition pore development, cellular viability, and apoptosis. Effects on the metabolism of the neurodegenerative disease pathogenic proteins alpha-synuclein, beta-amyloid, and tau, including tau phosphorylation, are particularly addressed, with application to Alzheimer's and Parkinson's diseases. Limitations of the current data are detailed and predictive criteria for translational clinical neuroprotection are proposed and discussed. Drugs that warrant further study for neuroprotection in neurodegenerative disease include pramipexole, thioridazine, risperidone, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, fluoxetine, buspirone, clonazepam, diphenhydramine, and melatonin. Those with multiple neuroprotective mechanisms include pramipexole, thioridazine, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, clonazepam, and melatonin. Those best viewed circumspectly in neurodegenerative disease until clinical disease course outcomes data become available, include several antipsychotics, lithium, oxcarbazepine, valproate, several tricyclic antidepressants, certain SSRIs, diazepam, and possibly diphenhydramine. A search for clinical studies of neuroprotection revealed only a single study demonstrating putatively positive results for ropinirole. An agenda for research on potentially neuroprotective agent is provided.

Neurodegenerative diseases such as Alzheimer’s disease involve regulated forms of cell death, including oxytosis/ferroptosis, which are driven by oxidative stress and neuroinflammation. Targeting these regulated cell death pathways offers novel therapeutic opportunities. Wyethia is a small genus of flowering plants native to North America, traditionally used by Indigenous populations for medicinal purposes. Its ethnobotanical relevance and phytochemical diversity prompted investigation into its neuroprotective potential. This study examined eight Wyethia species for anti-inflammatory and neuroprotective activities. We evaluated protection against oxytosis/ferroptosis (induced by glutamate, erastin, and RSL3) in HT22 neuronal cells, energy loss using an ischemia assay in HT22 cells, and LPS-induced inflammation in BV2 microglial cells. W. ovata, W. helenioides, W. amplexicaulis and W. glabra exhibited strong neuroprotection (EC50 < 25 μg/mL), with W. ovata also demonstrating potent anti-inflammatory activity (EC50 = 15.2 μg/mL). Antioxidant assays (DPPH, lipid peroxidation) and measurement of total phenolic content (TPC) analysis revealed a correlation between high phenolic content and antioxidant activity, with W. ovata and W. amplexicaulis showing the highest TPC values (120–140 mg GAE/g). However, W. invenusta displayed strong neuroprotective effects despite low TPC, suggesting that other bioactive compounds such as terpenoids, or alkaloids may contribute to its activity. This highlights the complexity of phytochemical profiles and the potential presence of potent constituents beyond phenolics. These findings position Wyethia as a promising source of dual-action neuroprotective agents that target both oxytosis/ferroptosis and inflammation, warranting further phytochemical investigation.

Repositioning of dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 receptor agonists is a breakthrough in the field of neural regeneration research increasing glucagon like peptide-1 bioavailability, hence its neuroprotective activities. In this article, the authors suggest not only crossing blood-brain barrier and neurodegenerative disease as off target for dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 receptor agonists, but also for ophthalmic preparations for diabetic retinopathy, which may be the latest breakthrough in the field if prepared and used in an appropriate nano-formulation to target the retinal nerves. The relation of neurodegenerative diseases’ different mechanisms to the dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 receptor agonists should be further examined in preclinical and clinical settings. The repositioning of already marketed antidiabetic drugs for neurodegenerative diseases should save the high cost of the time-consuming normal drug development process. Drug repositioning is a hot topic as an alternative to molecular target based drug discovery or therapeutic switching. It is a relatively inexpensive pathway due to availability of previous pharmacological and safety data. The glucagon like peptide-1 produced in brain has been linked to enhanced learning and memory functions as a physiologic regulator in central nervous system by restoring insulin signaling. Intranasal administration of all marketed gliptins (or glucagon like peptide-1 receptor agonists) may show enhanced blood-brain barrier crossing and increased glucagon like peptide-1 levels in the brain after direct crossing of the drug for the olfactory region, targeting the cerebrospinal fluid. Further blood-brain barrier crossing tests may extend dipeptidyl peptidase-4 inhibitors’ effects beyond the anti-hyperglycemic control to intranasal spray, intranasal powder, or drops targeting the blood-brain barrier and neurodegenerative diseases with the most suitable formula. Moreover, novel nano-formulation is encouraged either to obtain favorable pharmacokinetic parameters or to achieve promising blood-brain barrier penetration directly through the olfactory region. Many surfactants should be investigated either as a solubilizing agent for hydrophobic drugs or as penetration enhancers. Different formulae based on in vitro and in vivo characterizations, working on sister gliptins (or glucagon like peptide-1 receptor agonists), different routes of administration, pharmacokinetic studies, dose response relationship studies, monitoring of plasma/brain concentration ratio after single and multiple dose, and neurodegenerative disease animal models are required to prove the new method of use (utility) for dipeptidyl peptidase-4 inhibitors as potential neuroprotective agents. Furthermore, investigations of glucagon like peptide-1 receptor agonists’ neuroprotective effects on animal models will be considered carefully because they crossed the blood-brain barrier in previous studies, enabling their direct action on the central nervous system. Combination therapy of dipeptidyl peptidase-4 inhibitors or glucagon like peptide-1 receptor agonists with already marketed drugs for neurodegenerative disease should be considered, especially regarding the novel intranasal route of administration.

Event Abstract Back to Event Neuroprotective and Neurotherapeutic Effects of Bee Venom on Neurodegenerative Diseases Miran K. Rakha1* 1 Suez Canal University, Biotechnology Research Center, Egypt Acute and chronic neurodegenerative diseases are illnesses associated with high morbidity and mortality, and few or no effective options are available for their treatment. A characteristic of many neurodegenerative diseases — which include stroke, brain trauma, spinal cord injury, amyotrophic lateral sclerosis, Huntington’s disease, Alzheimer’s disease, and Parkinson’s disease — is neuronal cell death. Given that central nervous system tissue has very limited, if any, regenerative capacity, it is of utmost importance to limit the damage caused by neuronal death. Bee venom, which is also known as apitoxin, consists of several biologically active peptides, including melittin, adolapin, mast cell degranulating peptide and phospholipase A2. Moreover, bee venom contains a variety of bioamines, such as apamin, histamine, procamine, serotonin, and norepinephrine, which facilitate nerve transmission and healing in a variety of nerve disorders. This gives bee venom the ability to travel along the neural pathways from the spine to various trigger points and injured areas to help repair nerve damage and restore mobility. This review overviews; (1) causes and mechanisms of neurodegenerative diseases which pertains to neuronal cell death, (2) evidence linking composition comprising bee venom to its substantial potential for preventing and treating of neurodegenerative diseases associated with neuronal cell death, and (3) how improving our knowledge of the mechanisms mediating neuroprotective and neurotherapeutic activities of bee venom against neuronal cell death may led to novel therapeutic strategies for the treatment of neurodegenerative diseases. Future challenges remaining will be to elucidate signaling responses activated by bee venom in neurons. In other words, bee venom inhibits neuronal cell death and activation of proapoptotic signaling in neurons. These findings emphasize the clinical importance of bee venom for treatment of neurodegenerative diseases. Further investigation is necessary to elaborate the mechanisms involved and to permit full exploitation of neuroprotective and neurotherapeutic potentials of bee venom. References Doo AR et al. (2012): Bee venom protects SH-SY5Y human neuroblastoma cells from 1-methyl-4-phenylpyridinium-induced apoptotic cell death. Brain Res, 1429: 106-115. Lee SM et al. (2012): Effects of Bee Venom on Glutamate-Induced Toxicity in Neuronal and Glial Cells. Evidence-Based Complementary and Alternative Medicine, 2012: 368196, doi:10.1155/2012/368196. Rakha MK (2011): Impact of Beehive Products on the Cardiovascular Neurophysiology Expands Novel Horizons in Apitherapy. Conference Abstract: 10th Meeting of the Société des Neurosciences, May 24-27, 2011, Marseille, France. Yang EJ et al. (2011): Melittin restores proteasome function in an animal model of ALS. J Neuroinflammation, 8: 69, doi: 10.1186/1742-2094-8-69. Yang EJ et al. (2010): Bee venom attenuates neuroinflammatory events and extends survival in amyotrophic lateral sclerosis models. J Neuroinflammation, 7: 69, doi: 10.1186/1742-2094-7-69. Keywords: Bee Venom, Neuroprotective Activity, Neurotherapeutic Potential, Neuronal Cells, Neurodegenerative Diseases. Conference: 4th Conference of the Mediterrarnean Neuroscience Society, Istanbul, Turkey, 30 Sep - 3 Oct, 2012. Presentation Type: Poster Presentation Topic: Abstracts Citation: Rakha MK (2013). Neuroprotective and Neurotherapeutic Effects of Bee Venom on Neurodegenerative Diseases. Conference Abstract: 4th Conference of the Mediterrarnean Neuroscience Society. doi: 10.3389/conf.fnhum.2013.210.00057 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 26 Jan 2013; Published Online: 11 Apr 2013. * Correspondence: Dr. Miran K Rakha, Suez Canal University, Biotechnology Research Center, Ismailia, Egypt, mirankhalil@hotmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract Supplemental Data The Authors in Frontiers Miran K Rakha Google Miran K Rakha Google Scholar Miran K Rakha PubMed Miran K Rakha Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Shramahara Mahakasya, a traditional polyherbal formulation, induces anti-anxiety activity in hippocampal neurons by effectuating SOD2-mediated protection against oxidative stress

Oxidative stress is strongly involved in the pathogenesis of neurodegenerative diseases, like Parkinson´s disease (PD). Particularly, an excess of reactive oxygen species (ROS) released by the cells promotes an oxidative stress condition, which is a main cause of tissue injury leading to nervous system dysfunction. In this work, the antioxidant, neuroprotective and anti-inflammatory activities of different fractions from the brown seaweed Bifurcaria bifurcata are presented and related with their chemical profile. The antioxidant capacity was evaluated by the Folin-Ciocalteu method, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, ferric reducing antioxidant power (FRAP) and oxygen radical absorbance capacity (ORAC) assays. Neuroprotective capacity was evaluated to prevent neurological cell death mediated by the neurotoxin 6-hydroxydopamine (6-OHDA) on SH-SY5Y cells, and their anti-inflammatory effects on RAW 264.7 macrophages. The ethyl acetate fractions (100 µg mL−1) exhibited significant antioxidant and neuroprotective activities in the in vitro models assayed. Furthermore, two of the most polar fractions obtained with methanol and water also evidenced a significant neuroprotective potential. Bifurcaria bifurcata fractions treatment decreased ROS production, mitochondrial dysfunction, and Caspase-3 activity. Regarding the anti-inflammatory potential, five fractions (100 µg mL−1) inhibited nitric oxide (NO) production and reduced the interleukin – 6 (IL-6) and tumor necrosis factor (TNF-α) levels. Mannitol, identified as the major component of the most bioactive fraction, protected SH-SY5Y cells against the 6-OHDA neurotoxicity mediating ROS generation mitigation, mitochondrial dysfunction, and DNA damage, together with the Caspase-3 activity inhibition. Results suggest that B. bifurcata is a relevant source of neuroprotective agents, with particular interest for preventive therapeutics.

The neuroprotective and antioxidative activities of five organosulfur compounds with a thioallyl structure (-S-CH2CH=CH2) were characterized in terms of structure-activity relationships. Among five organosulfur compounds, only S-allyl-L-cysteine (SAC) having the alanyl group (-CH2CH-NH2-COOH) and lacking the oxo (O=) group with in between molecular properties, was effective in protecting cell death induced by both oxygen glucose deprivation and global cerebral ischemia. Conversely, lipophillic organosulfur compounds including diallyl sulfide, diallyl disulfide, and diallyl trisulfide were devoid of in vitro and in vivo neuroprotective activities. Furthermore, a significant correlation was only found between the in vivo neuroprotective activity and the OH- scavenging activity (gamma = 0.55 and p = 0.032) among reactive oxygen species scavenging activities. These results indicate that the presence of the alanyl group and the absence of the oxo group are essential for the manifestation of neuroprotective activity against ischemic insults and scavenging of OH radical, with SAC surfacing as a potent neuroprotectant.

Baicalein, a famously effective component of the traditional Chinese medicine Rhizoma Huang Qin (Scutellaria altissima L.), has been proved to have potent neuroprotection and anti-platelet aggregation effects with few side effects. Meanwhile, recent studies have revealed that the introduction of amino acid to baicalein could improve its neuroprotective activity. In the present study, a series of novel baicalein amino acid derivatives were designed, synthesized, and screened for their neuroprotective effect against tert-butyl, hydroperoxide-induced, SH-SY5Y neurotoxicity cells and toxicity on the normal H9C2 cell line by standard methylthiazol tetrazolium (MTT) assay. In addition, all of the newly synthesized compounds were characterized by 1H-NMR, 13C-NMR, and high resolution mass spectrometry (HR-MS). The results showed that most of the compounds provided more potent neuroprotection than baicalein, and were equivalent to the positive drug edaravin. They showed no obvious cytotoxicity on normal H9C2 cells. Notably, the most active compound 8 displayed the highest protective effect (50% effective concentration (EC50) = 4.31 μM) against tert-butyl, hydroperoxide-induced, SH-SY5Y neurotoxicity cells, which was much better than the baicalein (EC50 = 24.77 μM) and edaravin (EC50 = 5.62 μM). Further research on the chick chorioallantoic membrane (CAM) model indicated that compound 8 could significantly increase angiogenesis, which might promote neurovascular proliferation. The detection of apoptosis analysis showed that compound 8 could dramatically alleviate morphological manifestations of cell damage. Moreover, the benzyloxycarbonyl (cbz)-protected baicalein amino acid derivatives showed better neuroprotective activity than the t-Butyloxy carbonyl (boc)-protected derivatives.

Japanese encephalitis (JE) is the most common viral encephalitis caused by the Japanese encephalitis virus (JEV), primarily affecting children. Currently, there is no approved and effective antiviral drug against JEV infection. Diallyl disulfide (DADS) exerts antiviral activity against dengue virus, one of the Flavivirus. To establish the antiviral and neuroprotective potential of DADS against JEV. The present study explored the neuroprotective and antiviral activities of DADS in JEV-challenged SH-SY5Y cells in pre-, post-, and co-treatment approaches. Further, the study also investigated the nature of interaction between DADS and four drug targets of JEV such as envelope protein, NS3 helicase, NS3 protease, and NS5 RdRp using virtual screening. In plaque yield reduction assay, DADS significantly reduced plaque titer by 59.8% in post-treatment with median inhibitory concentrations of 165.8µM. A similar antiviral effect was observed in an immunocytochemistry assay in post-infection treatment mode. The in vitro antiviral activity of DADS was further supported by its robust binding affinity for NS3 Helicase and RNA-dependent RNA polymerase, highlighting DADS as a multi-target therapeutic agent. Significant neuroprotective activity was also observed in post-treatment methods, with cell viability of 75.87%, 79.15%, and 85.05% at 50, 100, and 200µM concentrations, respectively. The observed neuroprotective activities of the drug may be attributed to its antioxidant and anti-apoptotic activity in JEV-challenged cells. The network pharmacology analysis revealed key hub genes, including PTGS2, MAPK3, CCR2, MAOs, and DRD2, which may serve as drug targets for DADS to modulate JEV-induced immune dysregulation and neuroinflammation. This study has provided insight into the antiviral and neuroprotective potential of DADS against JEV. However, further in vivo and clinical studies are warranted to develop the drug as a therapeutic agent for the management of JE.

Neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, ischemia and traumatic injury are characterized by progressive neuronal loss and dysfunction. Many neuroprotective agents modulating cellular responses against noxious stimuli, such as oxidative stresses, thereby having anti-inflammatory and antiapoptotic activity have been studied to develop the therapeutics for neurodegenerative diseases. Recently, the phenolic compounds widely spread in medicinal plants have drawn attention as potential neuroprotective agents. In this review, naturally-occurring neuroprotective phenolics and their underlying mechanisms of neuroprotective actions are summarized.

IntroductionThe present study investigates the cholinesterase inhibitory and neuritogenic activities of selected essential oils from the Lamiaceae family, as well as their neuroprotective and antioxidant potential against scopolamine-induced cytotoxicity in SH-SY5Y cells. MethodsThe anticholinesterase activity was analysed using a modified Ellman’s assay. The neuroprotective potential was determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Intracellular reactive oxygen species (ROS) levels were quantified using 2',7’- dichlorofluorescin diacetate assay. A neurite outgrowth assay was employed to evaluate the neuritogenic activity. ResultsOregano leaf (terpineol-type), peppermint leaf, rosemary, and sage essential oils have antibutyrylcholinesterase activity, while oregano leaf (phenol-type) essential oil has both acetylcholinesterase and butyrylcholinesterase inhibitory activities. Pretreatment with lavender flower essential oil (30 µg/mL), linalool, and linalyl acetate for 24 hours protects against scopolamine-induced toxicity. Linalool also displayed a significant decrease in intracellular ROS. The oregano leaf (terpineol-type), peppermint, rosemary, and sage essential oils at 100 µg/mL exhibited neuritogenic activity, with the highest activity being observed with oregano leaf (terpineol-type) essential oil. Discussion/ConclusionsEssential oils from plants of Lamiaceae family displayed anticholinesterase, neuroprotective, antioxidant, and neuritogenic activities. These properties demonstrate their potential as complementary treatments to prevent and/or delay dementia-related diseases such as Alzheimer’s disease.

The study aimed to explore the phytochemicals present in the aqueous and ethanolextracts of Asparagus racemosus Linn seeds by GC-MS and LC-MS analysis and to determine the neuro protective and antioxidant potential of both the extracts. The GC-MS and LC-MS analysis of the aqueous and ethanol seed extract indicated the presence of various chemical constituents such as ascorbic acid, hydroxycinnamic acid, fatty acids, pyroglutamic acid, pentanoic acid, decanoic acid, hexadecanoic acid, naphthalene, hydroxycinnamic acid, thiamine hydrochloride, coumaroyl putrescin, agrimol, epanorin, brevicarine, rubiadin, pyroglutamic acid, tyrosine derivative, linoleyl acetate etc. Neuroprotective effect of aqueous and ethanol extracts of Asparagus racemosus Linn seeds on SHSY5Y cell line was evaluated by MTT assay and the results showedthat ethanol extract of the plant got more neuroprotective activity on cell lines. The antioxidant results showed that both of the extracts had almost similar DPPH and ABTS radical scavenging. However, the ethanol extract had more potent antioxidant power than the aqueous extract. Study data suggest that whole plant of Asparagus racemosus Linn seeds possessed neuroprotective and anti-oxidative activities and the best neuroprotective and anti-oxidant activity being exhibited by the ethanolic extract of the plant.

To favor their replication, viruses express proteins that target diverse mammalian cellular pathways. Due to the limited size of many viral genomes, such proteins are endowed with multiple functions, which require targeting to different subcellular compartments. One salient example is the X protein of Borna disease virus, which is expressed both at the mitochondria and in the nucleus. Moreover, we recently demonstrated that mitochondrial X protein is neuroprotective. In this study, we sought to examine the mechanisms whereby the X protein transits between subcellular compartments and to define its localization signals, to enhance its mitochondrial accumulation and thus, potentially, its neuroprotective activity. We transfected plasmids expressing fusion proteins bearing different domains of X fused to enhanced green fluorescent protein (eGFP) and compared their subcellular localization to that of eGFP. We observed that the 5-16 domain of X was responsible for both nuclear export and mitochondrial targeting and identified critical residues for mitochondrial localization. We next took advantage of these findings and constructed mutant X proteins that were targeted only to the mitochondria. Such mutants exhibited enhanced neuroprotective properties in compartmented cultures of neurons grown in microfluidic chambers, thereby confirming the parallel between mitochondrial accumulation of the X protein and its neuroprotective potential.-Ferré C. A., Davezac, N., Thouard, A., Peyrin, J. M., Belenguer, P., Miquel, M.-C., Gonzalez-Dunia, D., Szelechowski, M. Manipulation of the N-terminal sequence of the Borna disease virus X protein improves its mitochondrial targeting and neuroprotective potential.