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

International audienceBrief periods of ischemia have been shown in many experimental setups to provide tolerance against ischemia in multiple organs including the brain, when administered before (preconditioning) or even after (postconditioning) the normally lethal ischemia. In addition to these so-called ischemic conditionings, many pharmacological and natural agents (e.g., chemicals and nutraceuticals) can also act as potent pre-and post-conditioners. Deriving from the original concept of ischemic preconditioning, these various conditioning paradigms may be promising as clinical-stage therapies for prevention of ischemic-related injury, especially stroke. As no proven experimentally identified strategy has translated into clinical success, the experimental induction of neuroprotection using these various conditioning paradigms has raised several questions, even before considering translation to clinical studies in humans. The first aim of the review is to consider key questions on preclinical studies of pre-or post-conditioning modalities including those induced by chemical or nutraceuticals. Second, we make the argument that several key issues can be addressed by a novel concept, nutraceutical preconditioning. Specifically, α-linolenic acid (alpha-linolenic acid [ALA] an omega-3 polyunsaturated fatty acid), contained in plant-derived edible products, is essential in the daily diet, and a body of work has identified ALA as a pre-and post-conditioner of the brain. Nutritional intervention and functional food development are an emerging direction for preventing stroke damage, offering the potential to improving clinical outcomes through activation of the endogenous protective mechanisms known collectively as conditioning

Chlortetracycline and Demeclocycline Inhibit Calpains and Protect Mouse Neurons against Glutamate Toxicity and Cerebral Ischemia

Minocycline is a potent neuroprotective tetracycline in animal models of cerebral ischemia. We examined the protective properties of chlortetracycline (CTC) and demeclocycline (DMC) and showed that these two tetracyclines were also potent neuroprotective against glutamate-induced neuronal death in vitro and cerebral ischemia in vivo. However, CTC and DMC appeared to confer neuroprotection through a unique mechanism compared with minocycline. Rather than inhibiting microglial activation and caspase, CTC and DMC suppressed calpain activities. In addition, CTC and DMC only weakly antagonized N-methyl-D-aspartate (NMDA) receptor activities causing 16 and 14%, respectively, inhibition of NMDA-induced whole cell currents and partially blocked NMDA-induced Ca2+ influx, commonly regarded as the major trigger of neuronal death. In vitro and in vivo experiments demonstrated that the two compounds selectively inhibited the activities of calpain I and II activated following glutamate treatment and cerebral ischemia. In contrast, minocycline did not significantly inhibit calpain activity. Taken together, these results suggested that CTC and DMC provide neuroprotection through suppression of a rise in intracellular Ca2+ and inhibition of calpains

26th Annual Computational Neuroscience Meeting (CNS*2017): Part 3 - Meeting Abstracts - Antwerp, Belgium. 15–20 July 2017

This work was produced as part of the activities of FAPESP Research,\ud Disseminations and Innovation Center for Neuromathematics (grant\ud 2013/07699-0, S. Paulo Research Foundation). NLK is supported by a\ud FAPESP postdoctoral fellowship (grant 2016/03855-5). ACR is partially\ud supported by a CNPq fellowship (grant 306251/2014-0)

On the role of Ca 2+ in cerebral ischemic preconditioning.

NRC publication: Ye

Neuroprotection against staurosporine by metalloporphyrins independent of antioxidant capability

Metalloporphyrin catalytic antioxidants are remarkably useful in protecting cells and tissues in a wide array of disease models, attributed primarily to functioning as superoxide dismutase (SOD) mimetics or by scavenging other reactive oxygen species (ROS). However, we recently showed that neuroprotection against Ca\ub2\u207a-dependent excitotoxic insults did not correlate with antioxidant strength or capability [25], raising the question of whether scavenging of ROS underlies neuroprotection in other types of neuronal injury. The protein kinase inhibitor staurosporine causes neuronal demise primarily by apoptosis. Neuroprotection from staurosporine by a limited number of metalloporphyrin antioxidants has previously been attributed to antioxidant action. In the current study, a wide array of anionic and cationic metalloporphyrins and porphyrins, ranging in antioxidant strength or capability, provided protection against staurosporine in cortical neuron and cerebellar granule neuron (CGN) culture. Neuroprotection did not correlate with antioxidant strength or capability. In CGN but not cortical neuron cultures, NMDA receptor antagonists also prevented neurotoxicity, so metalloporphyrins may also target this secondary mode of death induced by staurosporine. Neuroprotection observed with antioxidant-inactive controls raises the possibility of an additional, or perhaps alternative, mechanism by antioxidant analogs not involving ROS scavenging.Peer reviewed: YesNRC publication: Ye

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

International audienceAcute 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

Calcium overload

NRC publication: Ye

Neural mechanisms in the hemodynamic adjustment produced by pilocarpine in rats treated with adrenergic agonist and antagonist

A pilocarpina, uma droga classificada como um agonista colinergico muscarinico, age nas glandulas salivares, produzindo vasodilatacao e salivacao. Estudos recentes tem mostrado que grande parte da salivacao induzida pela pilocarpina depende de mecanismos cerebrais. A salivacao induzida pela pilocarpina pode ser inibida pela lesao de estruturas cerebrais anteriores, como a regiao anteroventral do terceiro ventriculo (AM), area septal (AS) ou hipotalamo lateral (HL). Um mecanismo inibitorio da salivacao induzida pela pilocarpina tambem muito estudado esta relacionado com receptores adrenergicos 2 e imidazolicos. A moxonidina, assim com a clonidina (agonistas adrenergicos 2 e imidazolicos), sao drogas anti-hipertensivas que quando administradas centralmente reduzem a salivacao induzida por pilocarpina. Alem de participarem do controle de mecanismos salivatorios, essas drogas tambem estao envolvidas na regulacao cardiovascular. Assim, foram objetivos deste trabalho: a) estudar as alteracoes hemodinamicas produzidas pela associacao de moxonidina (agonista de receptores adrenergicos 2 e imidazolicos) e -metil noradrenalina (agonista de receptores adrenergicos 2) injetada nos ventriculos cerebrais (ventriculo lateral - VL e quarto ventriculo - 4°V) sobre as respostas hemodinamicas produzidas pela pilocarpina (agonista colinergico) injetada no VL. b) investigar o papel dos receptores adrenergicos 2 nos efeitos hemodinamicos da associacao de moxonidina ou -metil noradrenalina injetada no VL ou 4° V seguido de pilocarpina no VL. Para tanto, foram utilizados ratos Wistar com canulas de aco inoxidavel implantadas nos ventriculos cerebrais: VL (volume de injecao 1 a 2 L) e/ou 4°V (volume de injecao 1 L). Os ratos foram anestesiados com uretana (1,2 g/kg, i.v.) e um cateter foi inserido na arteria femoral para registro de pressao arterial media (PAM) e frequencia cardiaca (FC). Sondas miniaturizadas foram posicionadas ao redor da arteria que irriga o complexo submandibular/sublingual, da arteria mesenterica superior, da arteria renal esquerda e da extremidade da aorta abdominal para registro de fluxo sanguineo pelo metodo da fluxometria Dopplera(au)BV UNIFESP: Teses e dissertaçõe

Competing approaches to excitotoxic neuroprotection by inert and catalytic antioxidant porphyrins.: Neurosci.Lett.

NRC publication: Ye