Excitatory and inhibitory amino acid neurotransmitters in stroke: from neurotoxicity to ischemic tolerance

Amantea, Diana; Bagetta, Giacinto

doi:10.1016/j.coph.2017.07.014

Cited by 68 publications

(40 citation statements)

References 98 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Rekling (2003) previously reported that phenobarbital and chlordiazepoxide inhibited oxygen-glucose deprivation induced cell death in rat hippocampal slices. These data are consistent with the hypothesis that potentiation of GABA A receptors could be an important underlying mechanism against excitotoxicity (Foster and Kemp, 2006; Amantea and Bagetta, 2017). However, co-incubation of MFA with either picrotoxin, a non-competitive GABA gated chloride channel blocker (Squires et al, 1983) or the competitive GABA A receptor antagonist, bicuculline (Johnston, 2013), had no effect on the efficacy of MFA to inhibit glutamate-induced cell death.…”

Section: Discussionsupporting

confidence: 92%

Mechanisms Underlying Neuroprotection by the NSAID Mefenamic Acid in an Experimental Model of Stroke

Khansari

Halliwell

2019

Front. Neurosci.

View full text Add to dashboard Cite

Stroke is a devastating neurological event with limited treatment opportunities. Recent advances in understanding the underlying pathogenesis of cerebral ischemia support the involvement of multiple biochemical pathways in the development of the ischemic damage. Fenamates are classical non-steroidal anti-inflammatory drugs but they are also highly subunit-selective modulators of GABAA receptors, activators of IKS potassium channels and antagonists of non-selective cation channels and the NLRP3 inflammosome. In the present study we investigated the effect of mefenamic acid (MFA) in a rodent model of ischemic stroke and then addressed the underlying pharmacological mechanisms in vitro for its actions in vivo. The efficacy of MFA in reducing ischemic damage was evaluated in adult male Wistar rats subjected to a 2-h middle cerebral artery occlusion. Intracerebroventricular (ICV) infusion of MFA (0.5 or 1 mg/kg) for 24 h, significantly reduced the infarct volume and the total ischemic brain damage. In vitro, the fenamates, MFA, meclofenamic acid, niflumic acid, and flufenamic acid each reduced glutamate-evoked excitotoxicity in cultured embryonic rat hippocampal neurons supporting the idea that this is a drug class action. In contrast the non-fenamate NSAIDs, ibuprofen and indomethacin did not reduce excitotoxicity in vitro indicating that neuroprotection by MFA was not dependent upon anti-inflammatory actions. Co-application of MFA (100 μM) with either of the GABAA antagonists picrotoxin (100 μM) or bicuculline (10 μM) or the potassium channel blocker tetraethylammonium (30 mM) did not prevent neuroprotection with MFA, suggesting that the actions of MFA also do not depend on GABAA receptor modulation or potassium channel activation. These new findings indicate that fenamates may be valuable in the adjunctive treatment of ischemic stroke.

show abstract

Section: Discussionsupporting

confidence: 92%

Mechanisms Underlying Neuroprotection by the NSAID Mefenamic Acid in an Experimental Model of Stroke

Khansari

Halliwell

2019

Front. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Additionally, use of D 2 -class antagonists, though not D 1 -class antagonists, have been reported to have a protective effect on neurons in the striatum (Hashimoto et al, 1994 ; Okada et al, 2005 ; Yulug et al, 2006a , b ). In light of the well-established role of excessive glutamate release and sustained activation of extrasynaptic glutamate N-methyl-D-aspartate receptors (NMDAR) in mediating excitotoxicity and cell death during ischemic stroke, it remains unclear how the reported complex functional interactions between NMDARs and DA receptors contribute to either mitigating or exacerbating their deleterious effects (Wang et al, 2012 ; Brassai et al, 2015 ; Amantea and Bagetta, 2017 ).…”

Section: Effect Of Stroke On Functioning Of the Dopaminergic Systemmentioning

confidence: 99%

The Intersection of Central Dopamine System and Stroke: Potential Avenues Aiming at Enhancement of Motor Recovery

Gower

Tiberi

2018

Front. Synaptic Neurosci.

View full text Add to dashboard Cite

Dopamine, a major neurotransmitter, plays a role in a wide range of brain sensorimotor functions. Parkinson's disease and schizophrenia are two major human neuropsychiatric disorders typically associated with dysfunctional dopamine activity levels, which can be alleviated through the druggability of the dopaminergic systems. Meanwhile, several studies suggest that optimal brain dopamine activity levels are also significantly impacted in other serious neurological conditions, notably stroke, but this has yet to be fully appreciated at both basic and clinical research levels. This is of utmost importance as there is a need for better treatments to improve recovery from stroke. Here, we discuss the state of knowledge regarding the modulation of dopaminergic systems following stroke, and the use of dopamine boosting therapies in animal stroke models to improve stroke recovery. Indeed, studies in animals and humans show stroke leads to changes in dopamine functioning. Moreover, evidence from animal stroke models suggests stimulation of dopamine receptors may be a promising therapeutic approach for enhancing motor recovery from stroke. With respect to the latter, we discuss the evidence for several possible receptor-linked mechanisms by which improved motor recovery may be mediated. One avenue of particular promise is the subtype-selective stimulation of dopamine receptors in conjunction with physical therapy. However, results from clinical trials so far have been more mixed due to a number of potential reasons including, targeting of the wrong patient populations and use of drugs which modulate a wide array of receptors. Notwithstanding these issues, it is hoped that future research endeavors will assist in the development of more refined dopaminergic therapeutic approaches to enhance stroke recovery.

show abstract

“…Excitatory neurotransmitters are released in the extracellular space, reaching concentrations that are toxic to neurons. Excitotoxicity, Ca 2+ -dependent activation of detrimental enzymes, excessive production of reactive oxygen species (ROS) and inflammation represent crucial mechanisms underlying blood-brain barrier (BBB) disruption and neuronal death in the ischemic brain (Benveniste et al, 1984 ; Rothman and Olney, 1986 ; Butcher et al, 1990 ; Bano and Nicotera, 2007 ; Anrather and Iadecola, 2016 ; Curcio et al, 2016 ; Amantea and Bagetta, 2017 ). At least in experimental model systems, the ischemic insult results in upregulation of diverse programmed cell death pathways, whereby the active crosstalk between apoptosis, necroptosis, and autophagy pathways ultimately affects cellular fate (Yuan and Yankner, 2000 ; Wang et al, 2018 ).…”

Section: From Neuroprotection To Immunomodulationmentioning

confidence: 99%

Paradigm Shift to Neuroimmunomodulation for Translational Neuroprotection in Stroke

Amantea

Greco²,

Micieli³

et al. 2018

Front. Neurosci.

Self Cite

View full text Add to dashboard Cite

The treatment of acute ischemic stroke is still an unresolved clinical problem since the only approved therapeutic intervention relies on early blood flow restoration through pharmacological thrombolysis, mechanical thrombus removal, or a combination of both strategies. Due to their numerous complications and to the narrow time-window for the intervention, only a minority of stroke patients can actually benefit from revascularization procedures, highlighting the urgent need of identifying novel strategies to prevent the progression of an irreversible damage in the ischemic penumbra. During the past three decades, the attempts to target the pathways implicated in the ischemic cascade (e.g., excitotoxicity, calcium channels overactivation, reactive oxygen species (ROS) production) have failed in the clinical setting. Based on a better understanding of the pathobiological mechanisms and on a critical reappraisal of most failed trials, numerous findings from animal studies have demonstrated that targeting the immune system may represent a promising approach to achieve neuroprotection in stroke. In particular, given the dualistic role of distinct components of both the innate and adaptive arms of the immune system, a strategic intervention should be aimed at establishing the right equilibrium between inflammatory and reparative mechanisms, taking into consideration their spatio-temporal recruitment after the ischemic insult. Thus, the application of immunomodulatory drugs and their ability to ameliorate outcomes deserve validation in patients with acute ischemic stroke.

show abstract

Excitatory and inhibitory amino acid neurotransmitters in stroke: from neurotoxicity to ischemic tolerance

Cited by 68 publications

References 98 publications

Mechanisms Underlying Neuroprotection by the NSAID Mefenamic Acid in an Experimental Model of Stroke

Mechanisms Underlying Neuroprotection by the NSAID Mefenamic Acid in an Experimental Model of Stroke

The Intersection of Central Dopamine System and Stroke: Potential Avenues Aiming at Enhancement of Motor Recovery

Paradigm Shift to Neuroimmunomodulation for Translational Neuroprotection in Stroke

Contact Info

Product

Resources

About