Joseph S Tauskela’s research while affiliated with National Research Council Canada and other places

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Publications (64)


Optimization of Cell Penetrating Poly-Arginine Peptides to Provide a Superior Therapeutic Index Against Severe Excitotoxic Insults In Vitro
  • Conference Paper

December 2024

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1 Read

Joseph S Tauskela

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Amy Aylsworth

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Introduction A body of work in our laboratory suggests that neuroprotective drugs should be tested against increasingly stringent models of cerebral ischemia in order to identify the drug(s) and dose providing the highest therapeutic index (‘last man standing’). It is within this context that we have evaluated peptides, specifically arginine (R)-rich cell-penetrating peptides (CPPs), which have recently emerged as promising neuroprotective candidates. Conjugation of the well-known TAT (GRKKRRQRRRPQ) CPP with various peptide cargoes has provided neuroprotection against stroke-like insults in vitro and in vivo [1]. Surprisingly, arginine-rich CPPs on their own (i.e., without cargo) were reported to provide better neuroprotection than TAT-NR2B9c against stroke-like insults, particularly CPPs containing more R residues [2,3]. Maximal neuroprotection was achieved with R18 (currently in a phase II stroke clinical trial). The mechanism of neuroprotection was attributed primarily to neuronal entry of oligoarginine peptides causing concomitant withdrawal of NMDA receptors from the plasma membrane, in turn reducing excitotoxic Ca2+ influx [4]. Methods We now show that poly-arginine peptides are actually quite limited in the degree of neuroprotection conferred. Specifically, neurotoxic Ca2+ influx is no longer suppressed if the in vitro excitotoxic insult is prolonged or intense. Moreover, R18 alone caused synaptotoxicity at relatively higher doses, judged using multi-electrode arrays. Results Thus, the therapeutic index of current CPPs may be too limited: TAT-conjugated peptides may display insufficient efficacy, while the higher doses of long-chain oligoarginines required to improve neuroprotection approaches a neurotoxic threshold. We now identify a class of alkyl-polyarginine peptides which improves against these limitations. Compared to R18, acylated-R9 peptides provided more potent neuroprotection against prolonged/intense in vitro insults at equimolar doses, which was below the synaptotoxic threshold relative to R18. Testing acyl chain lengths from C4 to C14 in R9 peptides yielded the optimal therapeutic index was produced by C10-R9 or C12-R9. R9 alone caused neuronal plasma membrane hyperpolarization. Plasma membrane hyperpolarization enhances cell penetration by CPPs, but also inactivates NMDA receptors. Conclusion These findings do not support a mechanism requiring reduced cell surface NMDA receptors, but instead suggest a plasma membrane hyperpolarization based mechanism resulting in a superior therapeutic index provided by acyl-R9’s.


Fig. 2. Surface preparation and formation of dual-organoid platforms. (a) Illustration of surface treatments for generation of IOPs given in cross-section. (b) Water contact angles of hydrophobic and hydrophilic domains given with representative droplets. (c) Top-down view schematics of the mask and resulting geometry of the dual-organoid platform. (d) Immunostaining of an IOP for TUBB3 at 15 DPD.
Fig. 3. Characterization of DOPs at 30 DPD. (a) Immunofluorescence of GAD67 and TUBB3 of striatal organoid. (b) DARPP32 and TUBB3 staining of striatal organoids. Images of replicated DOPs were given in the same panel displaying DARPP32 expression consistently stronger on the edge facing the midbrain organoid. Scale bar 100 μm. (c) Maximum projection image of a single DOP showing both organoids and IOP stained for TH and TUBB3. (d) Close-up image of IOP displaying TH expression. (e) Western blots showing dopamine receptors and TH expression in midbrain and striatal organoids of the same DOP. (f) GFAP and MAP2 staining of midbrain and striatal organoids showing the distribution of neuronal and glial populations. (g) GFP signal observed after VSV-GFP injection into the midbrain organoid given together with synaptophysin staining.
Fig. 4. Microelectrode array (MEA) measurements obtained from IOPs and single midbrain organoids. At least 30 samples were recorded for each experiment. (a) IOPs showing the progression of electrical activity maturation in mean firing rate plot given with representative brightfield image of IOP at 25 DPD. (b) Change of IOP activity from baseline 20 min after treatment with D2 dopamine receptor and GABAA receptor blockers displayed in truncated violin plots. (c) 6-OHDA (10 μM) treatment characterization comparing before and 24 h after treatment of IOPs and single midbrain organoids. Representative raster plots were given with firing rate change from baseline at the single electrode and IOP level. Percentage of completely silenced units in each midbrain organoid and IOP were calculated by spike sorting and determining the number of actively firing units. d) Intensity profile of calcium transients over a period of 30 s (85 cycles) and the correlating region of interests (area = 9048 μm 2 ) displayed on Fluo-4, AM loaded organoids, representative from 20 DOPs.
Unraveling the assembloid: Real-time monitoring of dopaminergic neurites in an inter-organoid pathway connecting midbrain and striatal regions
  • Article
  • Full-text available

February 2024

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125 Reads

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5 Citations

Materials Today Bio

Modern in vitro technologies for preclinical research, including organ-on-a-chip, organoids- and assembloid-based systems, have rapidly emerged as pivotal tools for elucidating disease mechanisms and assessing the efficacy of putative therapeutics. In this context, advanced in vitro models of Parkinson's Disease (PD) offer the potential to accelerate drug discovery by enabling effective platforms that recapitulate both physiological and pathological attributes of the in vivo environment. Although these systems often aim at replicating the PD-associated loss of dopaminergic (DA) neurons, only a few have modelled the degradation of dopaminergic pathways as a way to mimic the disruption of downstream regulation mechanisms that define the characteristic motor symptoms of the disease. To this end, assembloids have been successfully employed to recapitulate neuronal pathways between distinct brain regions. However, the investigation and characterization of these connections through neural tracing and electrophysiological analysis remain a technically challenging and time-consuming process. Here, we present a novel bioengineered platform consisting of surface-grown midbrain and striatal organoids at opposite sides of a self-assembled DA pathway. In particular, dopaminergic neurons and striatal GABAergic neurons spontaneously form DA connections across a microelectrode array (MEA), specifically integrated for the real-time monitoring of electrophysiological development and stimuli response. Calcium imaging data showed spiking synchronicity of the two organoids forming the inter-organoid pathways (IOPs) demonstrating that they are functionally connected. MEA recordings confirm a more robust response to the DA neurotoxin 6-OHDA compared to midbrain organoids alone, thereby validating the potential of this technology to generate highly tractable, easily extractable real-time functional readouts to investigate the dysfunctional dopaminergic network of PD patients.

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Improved Cryopreservation of Human Induced Pluripotent Stem Cell (iPSC) and iPSC-derived Neurons Using Ice-Recrystallization Inhibitors

August 2023

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119 Reads

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2 Citations

Stem Cells

Human induced pluripotent stem cells (iPSCs) and iPSC-derived neurons (iPSC-Ns) represent a differentiated modality toward developing novel cell-based therapies for regenerative medicine. However, the successful application of iPSC-Ns in cell-replacement therapies relies on effective cryopreservation. In this study, we investigated the role of ice recrystallization inhibitors (IRIs) as novel cryoprotectants for iPSCs and terminally differentiated iPSC-Ns. We found that one class of IRIs, N-aryl-D-aldonamides (specifically 2FA), increased iPSC post-thaw viability and recovery with no adverse effect on iPSC pluripotency. While 2FA supplementation did not significantly improve iPSC-N cell post-thaw viability, we observed that 2FA cryopreserved iPSC-Ns re-established robust neuronal network activity and synaptic function much earlier compared to CS10 cryopreserved controls. The 2FA cryopreserved iPSC-Ns retained expression of key neuronal specific and terminally differentiated markers and displayed functional electrophysiological and neuropharmacological responses following treatment with neuroactive agonists and antagonists. We demonstrate how optimizing cryopreservation media formulations with IRI represents a promising strategy to improve functional cryopreservation of iPSCs and post-mitotic iPSC-Ns, the latter which have been challenging to achieve. Developing IRI enabling technologies to support an effective cryopreservation and an efficiently managed cryo-chain is fundamental to support the delivery of successful iPSC-derived therapies to the clinic.


Neuroprotection against supra-lethal ‘stroke in a dish’ insults by an anti-excitotoxic receptor antagonist cocktail

June 2022

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22 Reads

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3 Citations

Neurochemistry International

The goal of this study was to identify cocktails of drugs able to protect cultured rodent cortical neurons against increasing durations of oxygen-glucose deprivation (OGD). As expected, a cocktail composed of an NMDA and AMPA receptor antagonists and a voltage gated Ca2+ channel blocker (MK-801, CNQX and nifedipine, respectively) provided complete neuroprotection against mild OGD. Increasingly longer durations of OGD necessitated increasing the doses of MK-801 and CNQX, until these cocktails ultimately failed to provide neuroprotection against supra-lethal OGD, even at maximal drug concentrations. Surprisingly, supplementation of any of these cocktails with blockers of TRPM7 channels for increasing OGD durations was not neuroprotective, unless these blockers possessed the ability to inhibit NMDA receptors. Supplementation of the maximally effective cocktail with other NMDA receptor antagonists augmented neuroprotection, suggesting insufficient NMDAR blockade by MK-801. Substitution of MK-801 in cocktails with high concentrations of a glycine site NMDA receptor antagonist caused the greatest improvements in neuroprotection, with the more potent SM-31900 superior to L689,560. Substitution of CQNX in cocktails with AMPA receptor antagonists at high concentrations also improved neuroprotection, particularly with the combination of SYM 2206 and NBQX. The most neuroprotective cocktail was thus composed of SM-31900, SYM2206, NBQX, nifedipine and the antioxidant trolox. Thus, the cumulative properties of antagonist potency and concentration in a cocktail dictate neuroprotective efficacy. The central target of supra-lethal OGD is excitotoxicity, which must be blocked to the greatest extent possible to minimize ion influx.



Differentiation and characterization of AF-iNs grown on PLO. A Schematic depicting AF-iNs CNS differentiation protocol and timeline. B Immunofluorescence staining with neuronal markers MAP-2, NeuN, βIII-Tubulin, NCAM, VGLUT2, Synaptophysin, Synaptotagmin, NMDAR-1, GAD65 + 67, GABAA (red) and astrocyte marker GFAP (green). Hoechst (Blue) counter stain. Scale bar = 20 µm
Physiological properties of AF-iN (A–D), primary rat cortical neurons (E) and primary human neurons (ScienCell™) (F). A top and C top Voltage response of two AF-iNs to graded series of intracellular current pulses (bottom). The current pulses were applied at − 52 mV (A) and − 80 mV (C). B, D Spontaneous activity recorded at resting membrane potential (Vmrest) in the same neurons as in (A, C). E Voltage response of a primary rat cortical neuron to graded series of intracellular current pulses (bottom). The current pulses were applied at voltage membrane rest (Vm rest =  − 58 mV). F Voltage response of a primary human neuron (ScienCell™) after 27 days in culture to graded series of intracellular current pulses (bottom). The current pulses were applied at voltage membrane rest (Vm rest =  − 55 mV)
Comparison of pharmacological responsiveness of AF-iN, CNS.4U and rat primary cortical neurons. A Representative spike Raster plots showing developmental profile of spontaneous activity in a representative MEA of AF-iNs on PLO. The y axis in each plot represents electrode number (1–59) and the x axis represents recording time (20 min). B Number of active electrodes and C median number of spikes per electrode of AF-iNs showing a gradual increase in mean firing rate (MFR) over time in culture. D The plot of the correlations between electrophysiological parameters was created in R using the psych package. Scatterplots with regression lines of the log2 (fold change) values are in the lower left quadrant and are from the data in Table 3. Histograms with density plots of the data for each cell type are presented on the diagonal. The Pearson correlation coefficients are presented in the upper right panels, and significance is indicated. *P < 0.05; **P < 0.01; ***P < 0.001
Effect of drugs on mean firing rate (MFR) of primary rodent, human iPSC-derived CNS.4U and AF-iN cultures
Electrophysiological- and Neuropharmacological-Based Benchmarking of Human Induced Pluripotent Stem Cell-Derived and Primary Rodent Neurons

October 2021

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189 Reads

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8 Citations

Stem Cell Reviews and Reports

Human induced pluripotent stem cell (iPSC)-derived neurons are of interest for studying neurological disease mechanisms, developing potential therapies and deepening our understanding of the human nervous system. However, compared to an extensive history of practice with primary rodent neuron cultures, human iPSC-neurons still require more robust characterization of expression of neuronal receptors and ion channels and functional and predictive pharmacological responses. In this study, we differentiated human amniotic fluid-derived iPSCs into a mixed population of neurons (AF-iNs). Functional assessments were performed by evaluating electrophysiological (patch-clamp) properties and the effect of a panel of neuropharmacological agents on spontaneous activity (multi-electrode arrays; MEAs). These electrophysiological data were benchmarked relative to commercially sourced human iPSC-derived neurons (CNS.4U from Ncardia), primary human neurons (ScienCell™) and primary rodent cortical/hippocampal neurons. Patch-clamp whole-cell recordings showed that mature AF-iNs generated repetitive firing of action potentials in response to depolarizations, similar to that of primary rodent cortical/hippocampal neurons, with nearly half of the neurons displaying spontaneous post-synaptic currents. Immunochemical and MEA-based analyses indicated that AF-iNs were composed of functional glutamatergic excitatory and inhibitory GABAergic neurons. Principal component analysis of MEA data indicated that human AF-iN and rat neurons exhibited distinct pharmacological and electrophysiological properties. Collectively, this study establishes a necessary prerequisite for AF-iNs as a human neuron culture model suitable for pharmacological studies. Graphic Abstract


Resilience of network activity in preconditioned neurons exposed to ‘stroke-in-a-dish’ insults

March 2021

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41 Reads

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1 Citation

Neurochemistry International

Exposing cultured cortical neurons to stimulatory agents - the K⁺ channel blocker 4-aminopyridine (4-ap), and the GABAA receptor antagonist bicuculline (bic) - for 48 h induces down-regulated synaptic scaling, and preconditions neurons to withstand subsequent otherwise lethal ‘stroke-in-a-dish’ insults; however, the degree to which usual neuronal function remains is unknown. As a result, multi-electrode array and patch-clamp electrophysiological techniques were employed to characterize hallmarks of spontaneous synaptic activity during over a 12-day preconditioning/insult experiment. Spiking frequency increased 8-fold immediately upon 4-ap/bic treatment but declined within the 48 h treatment window to sub-baseline levels that persisted long after washout. Preconditioning resulted in key markers of network activity – spiking frequency, bursting and avalanches – being impervious to an insult. Surprisingly, preconditioning resulted in higher peak NMDA mEPSC amplitudes, resulting in a decrease in the ratio of AMPA:NMDA mEPSC currents, suggesting a relative increase in synaptic NMDA receptors. An investigation of a broad mRNA panel of excitatory and inhibitory signaling mediators indicated preconditioning rapidly up-regulated GABA synthesis (GAD67) and BDNF, followed by up-regulation of neuronal activity-regulated pentraxin and down-regulation of presynaptic glutamate release (VGLUT1). Preconditioning also enhanced surface expression of GLT-1, which persisted following an insult. Overall, preconditioning resulted in a reduced spiking frequency which was impervious to subsequent exposure to ‘stroke-in-a-dish’ insults, a phenotype initiated predominantly by up-regulation of inhibitory neurotransmission, a lower neuronal postsynaptic AMPA: NMDA receptor ratio, and trafficking of GLT-1 to astrocyte plasma membranes.


Pre‐clinical development of a blood‐brain barrier (BBB)‐penetrating anti‐amyloid‒β fusion protein: Nonhuman/Target identification and validation studies: Amyloid

December 2020

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72 Reads

Background We have developed a blood‐brain barrier (BBB) crossing anti‐amyloid fusion protein KG207 as a potential AD therapeutic. This humanized bi‐functional molecule was generated by fusing an Aß oligomer (AßO)‐ binding peptide (ABP) with a BBB carrier FC5 via IgG‐1 Fc fragment. Present study shows that KG207 crosses the BBB in vitro and in vivo (mouse, rat and dog), penetrates target regions of the brain (cortex and hippocampus) and engages parenchymal Aß. KG207 neutralizes AßO‐induced toxicity in vitro and does not stimulate pro‐inflammatory cytokine production in mouse microglia. Studies demonstrated that KG207 was safe up to 300 mg/kg. Method Recombinant KG207 was produced in CHO cells. BBB‐permeability was assessed using in vitro BBB (formed by rat or human brain endothelial cells) and in vivo (rat, mouse and dog) models. AßO binding was determined by ELISA. Following iv injection, serum, CSF and brain levels of KG207 and Aß were assessed by nanoLC‐ MRM, ELISA and Western blot methods. Aß toxicity studies were done in human neuroblastoma (SH‐SY5Y) cells and rat primary cortical neuronal cells. Following exposure to KG207, cytokine levels in BV2 microglia were measured using Millipore Luminex assay kit. Safety studies were done in Sprague Dawley rats at 30, 100 and 300 mg/kg. Result KG207 retained both Aß‐oligomer binding activity and BBB‐permeability in vitro . When injected iv into rats and mouse, KG207 rapidly appeared in the CSF and brain parenchyma (cortex and hippocampus) indicating active transport of ABP across BBB by FC5 in vivo . In AD transgenic mice, KG207 treatment showed a significant reduction of brain Aß levels. KG207 significantly reduced AßO‐induced toxicity in both human neuroblastoma cells and primary cortical neurons in vitro . KG207 blocked AßO binding to cellular proteins in vitro . KG207 did not activate BV2 mouse microglia and induce pro‐inflammatory cytokines. No adverse effects were seen in rats injected with up to 300 mg/kg, including neurotoxicity. Conclusion Collectively, these results indicate that KG207 can effectivey cross the blood‐brain barrier, penetrate the brain and facilitate Aß clearance in vivo . In vitro data suggest that KG207 can safely clear Aß without eliciting pro‐inflammatory cytokine secretion by microglia.


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Requirement for preclinical prioritization of neuroprotective strategies in stroke: Incorporation of preconditioning

April 2018

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109 Reads

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4 Citations

Acute neuroprotection in numerous human clinical trials has been an abject failure. Major systemic-and procedural-based issues have subsequently been identified in both clinical trials and preclinical animal model experimentation. As well, issues related to the neuroprotective moiety itself have contributed to clinical trial failures, including late delivery, mono-targeting, low potency and poor tolerability. Conditioning (pre-or post-) strategies can potentially address these issues and are therefore gaining increasing attention as approaches to protect the brain from cerebral ischemia. In principle, conditioning can address concerns of timing (preconditioning could be pre-emptively applied in high-risk patients, and post-conditioning after patients experience an unannounced brain infarction) and signaling (multi-modal). However, acute neuroprotection and conditioning strategies face a common translational issue: a myriad of possibilities exist, but with no strategy to select optimal candidates. In this review, we argue that what is required is a neuroprotective framework to identify the "best" agent(s), at the earliest investigational stage possible. This may require switching mindsets from identifying how neuroprotection can be achieved to determining how neuroprotection can fail, for the vast majority of candidates. Understanding the basis for failure can in turn guide supplementary treatment, thereby forming an evidence-based rationale for selecting combinations of therapies. An appropriately designed in vitro (neuron culture, brain slices) approach, based on increasing the harshness of the ischemic-like insult, can be useful in identifying the "best" conditioner or acute neuroprotective therapy, as well as how the two modalities can be combined to overcome individual limitations. This would serve as a base from which to launch further investigation into therapies required to protect the neurovascular unit in in vivo animal models of cerebral ischemia. Based on these respective approaches, our laboratories suggest that there is merit in examining synaptic activity-and nutraceutical-based preconditioning / acute neuroprotection.


Analysis of the pharmacological properties of JWH-122 isomers and THJ-2201, RCS-4 and AB-CHMINACA in HEK293T cells and hippocampal neurons

February 2018

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71 Reads

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11 Citations

European Journal of Pharmacology

Synthetic cannabinoids are marketed as legal alternatives to Δ9-THC, and are a growing worldwide concern as these drugs are associated with severe adverse effects. Unfortunately, insufficient information regarding the physiological and pharmacological effects of emerging synthetic cannabinoids (ESCs) makes their regulation by government authorities difficult. One strategy used to evade regulation is to distribute isomers of regulated synthetic cannabinoids. This study characterized the pharmacological properties of a panel of ESCs in comparison to Δ9-THC, as well as six JWH-122 isomers relative to its parent compound (JWH-122-4). Two cell-based assays were used to determine the potency and efficacy of ESCs and a panel of reference cannabinoids. HEK293T cells were transfected with human cannabinoid receptor 1 (CB1) and pGloSensor-22F, and the inhibition of forskolin-stimulated cyclic adenosine monophosphate (cAMP) levels was monitored in live cells. All ESCs examined were classified as agonists, with the following rank order of potency: Win 55,212-2 > CP 55,940 > JWH-122-4 > Δ9-THC ≈ RCS-4 ≈ THJ-2201 > JWH-122-5 > JWH-122-7 > JWH-122-2 ≈ AB-CHMINACA > JWH-122-8 > JWH-122-6 > JWH-122-3. Evaluation of ESC-stimulated Ca2+ transients in cultured rat primary hippocampal neurons confirmed the efficacy of four of the most potent ESCs (JWH-122-4, JWH-122-5, JWH-122-7 and AB-CHMINACA). This work helps regulatory agencies make informed decisions concerning these poorly characterized recreational drugs.


Citations (48)


... Organoids are playing an increasingly important role in preclinical research, including studies into neurodegenerative diseases [17][18][19] . Organoids derived from the airway epithelium have gained prominence for studying diseases affecting respiratory tissues such as the lung 20 and nasal 21 epithelia. ...

Reference:

A Protocol for Neuralized Murine Olfactory Organoids
Unraveling the assembloid: Real-time monitoring of dopaminergic neurites in an inter-organoid pathway connecting midbrain and striatal regions

Materials Today Bio

... Ice recrystallization inhibitors (IRIs) are small molecules that aid the cryoprotective action by maintaining small ice crystal size within a frozen solution [8,13]. IRIs have shown promising results in mitigating cellular damages in pluripotent stem cells [14,15]. They are easily synthesized, tuneable, amenable to industrial production, and have been demonstrated not to be cytotoxic [15,16]. ...

Improved Cryopreservation of Human Induced Pluripotent Stem Cell (iPSC) and iPSC-derived Neurons Using Ice-Recrystallization Inhibitors
  • Citing Article
  • August 2023

Stem Cells

... Data are expressed as mean ± SEM. (*p < 0.05, **p < 0.01, n = 6.) series of downstream pro-death signaling events, treatment against excitotoxicity is a promising strategy on neuronal injuries upon ischemic stress (Lai, Zhang et al. 2014). Given the important role of NMDARs in excitotoxicity, many previous studies have focused on blockade the NMDA receptors (Tauskela et al. 2022). There are several pharmacologically available sites on the NMDARs, including ion channel pores, glutamate-binding sites, and glycine-binding sites, which are the target sites of NMDA receptor antagonists (Monaghan et al. 2012). ...

Neuroprotection against supra-lethal ‘stroke in a dish’ insults by an anti-excitotoxic receptor antagonist cocktail
  • Citing Article
  • June 2022

Neurochemistry International

... Intrinsic activity in iPSC-derived neurons is routinely investigated using single cell electrophysiological approaches, which offer accurate single-cell resolution within an in vitro neuronal population ( Table 2). Patch clamp techniques have been used in iPSC-derived neurons for the characterisation of intrinsic passive cellular properties, including membrane potential and membrane resistance, and active cellular properties, like firing rate and spontaneous activity (Halliwell et al. 2021;Jezierski et al. 2021). Together, the electrophysiological properties of iPSC-derived neurons can be used to characterise and classify neuronal cell types, monitor the maturity and degree of differentiation of iPSC-derived neurons and allow comparisons between cell lines (Halliwell et al. 2021;Jezierski et al. 2021;Vahsen et al. 2022;Smith et al. 2021;Taga et al. 2019). ...

Electrophysiological- and Neuropharmacological-Based Benchmarking of Human Induced Pluripotent Stem Cell-Derived and Primary Rodent Neurons

Stem Cell Reviews and Reports

... Rat cortical/hippocampal neurons adhered quite well to both PLL and PEI during development in culture; however, neurons plated on the latter coating appeared flatter and less bulbous after approximately 2 weeks. In contrast, cultures on PLL coated MEAs displayed minimal tendency to aggregate (Supplementary Fig. S1B) and showed robust synchronized bursting activity by 14-18 DIV [12,29]. All recordings examining responses to drugs were performed on cultures from 14 to 25 DIV. ...

Resilience of network activity in preconditioned neurons exposed to ‘stroke-in-a-dish’ insults
  • Citing Article
  • March 2021

Neurochemistry International

... Repeated intake of polyphenols has been reported to reduce subsequent cerebral ischemic injury in other experimental systems 22,23 . This phenomenon is known as preconditioning and is anticipated to be a new therapeutic approach for stroke in humans through healthy food consumption 24 . ...

Tackling issues in the path toward clinical translation in brain conditioning: Potential offered by nutraceuticals

Brain Circulation

... This could serve as a basis from which to launch further investigation into therapies for organ transplantation or any other predictable ischemia related injuries. One future avenue of examination in to preconditioning strategies (Tauskela and Blondeau, 2018) would be selecting combinations of therapies, including different preconditioning protocols that likely act through different pathways to obtain synergistic action with a better outcome of graft function. ...

Requirement for preclinical prioritization of neuroprotective strategies in stroke: Incorporation of preconditioning

... Unlike THC, some of these compounds have been associated with severe toxicological events, including seizures, cardiotoxicity, psychosis, hypothermia, and kidney injury, resulting in hundreds of hospitalizations and dozens of fatalities (Trecki et al., 2015;Adams et al., 2017). This increased morbidity and mortality of some of the SCRAs is correlated with a stronger efficacy for activation of the CB 1 receptor (Wiley et al., 2015;Banister et al., 2016;Cannaert et al., 2016;Hess et al., 2016;Costain et al., 2018;Gamage et al., 2018;Grafinger et al., 2021a,b). For example, the SCRA 5F-MDMB-PICA was recently shown to activate the CB 1 receptor with an efficacy 260-fold higher than that of THC, demonstrated using the operational model of agonism and varying levels of receptor expression (Sachdev et al., 2019). ...

Analysis of the pharmacological properties of JWH-122 isomers and THJ-2201, RCS-4 and AB-CHMINACA in HEK293T cells and hippocampal neurons
  • Citing Article
  • February 2018

European Journal of Pharmacology

... Among the small molecules identified, rapamycin was recognized as a significant CR mimetic, noted for its capacity to replicate the health benefits linked to CR (Madeo et al. 2019). Other enriched small molecules included linolenic acid, Rottlerin, estradiol, dasatinib, TWS119, rutin, nilotinib, dexamethasone, and trichostatin A, all of which have demonstrated neuroprotective properties in previous studies (Blondeau & Tauskela 2013;Fleiss et al. 2012;Azcoitia et al. 2011;Piermartiri et al. 2015;Zhou et al. 2007;Hwang et al. 2020;Gągało et al. 2015;Song et al. 2019;Budzynska et al. 2019;Karuppagounder et al. 2014; also indicating percentage cell viability. Statistical significance was evaluated by comparing OGD with control (*p < 0.001; #p < 0.05, n = 6), and treatment doses were compared with OGD to assess significance Content courtesy of Springer Nature, terms of use apply. ...

A new future in brain preconditioning based on nutraceuticals: A focus on a-linolenic omega-3 fatty acid for stroke protection
  • Citing Article
  • January 2013

... Currently, toxicity data on SCs and in particular on MAM-2201, which has been frequently identified in herbal blends or in powder products, are mainly obtained from studies performed on in vitro rodent cells and in vivo animal models [24][25][26]. The limited experimental evidence on neuronal cultures (rodent) indicate that MAM-2201 exposure can cause impairments of neuronal function and activity, as well as the inhibition of neurotransmitter release, which are effects likely mediated by the CB1 receptor [25,[27][28][29]. Moreover, abnormal behaviors have been observed in animal models [30]. ...

Effect of synthetic cannabinoids on spontaneous neuronal activity: Evaluation using Ca2+ spiking and multi-electrode arrays
  • Citing Article
  • June 2016

European Journal of Pharmacology