neuroprotective strategies
Recently Published Documents

With the onset of the COVID-19 pandemic, it became apparent that, in addition to pulmonary infection, extrapulmonary manifestations such as cardiac injury and acute cerebrovascular events are frequent in patients infected with SARS-CoV-2, worsening clinical outcome. We reviewed the current literature on the pathophysiology of cardiac injury and its association with acute ischaemic stroke. Several hypotheses on heart and brain axis pathology in the context of stroke related to COVID-19 were identified. Taken together, a combination of disease-related coagulopathy and systemic inflammation might cause endothelial damage and microvascular thrombosis, which in turn leads to structural myocardial damage. Cardiac complications of this damage such as tachyarrhythmia, myocardial infarction or cardiomyopathy, together with changes in hemodynamics and the coagulation system, may play a causal role in the increased stroke risk observed in COVID-19 patients. These hypotheses are supported by a growing body of evidence, but further research is necessary to fully understand the underlying pathophysiology and allow for the design of cardioprotective and neuroprotective strategies in this at risk population.

Two observations made 29 years apart are the cornerstones of this review on the contributions of Dr Gordon T. Plant to understanding pathology affecting the optic nerve. The first observation laid the anatomical basis in 1990 for the interpretation of optical coherence tomography (OCT) findings in 2009. Retinal OCT offers clinicians detailed in vivo structural imaging of individual retinal layers. This has led to novel observations which were impossible to make using ophthalmoscopy. The technique also helps to re-introduce the anatomically grounded concept of retinotopy to clinical practise. This review employs illustrations of the anatomical basis for retinotopy through detailed translational histological studies and multimodal brain-eye imaging studies. The paths of the prelaminar and postlaminar axons forming the optic nerve and their postsynaptic path from the dorsal lateral geniculate nucleus to the primary visual cortex in humans are described. With the mapped neuroanatomy in mind we use OCT-MRI pairings to discuss the patterns of neurodegeneration in eye and brain that are a consequence of the hard wired retinotopy: anterograde and retrograde axonal degeneration which can, within the visual system, propagate trans-synaptically. The technical advances of OCT and MRI for the first time enable us to trace axonal degeneration through the entire visual system at spectacular resolution. In conclusion, the neuroanatomical insights provided by the combination of OCT and MRI allows us to separate incidental findings from sinister pathology and provides new opportunities to tailor and monitor novel neuroprotective strategies.

Open-heart surgery is the leading cause of neuronal injury in the perioperative state, with some patients complicating with cerebrovascular accidents and delirium. Neurological fallout places an immense burden on the psychological well-being of the person affected, their family, and the healthcare system. Several randomised control trials (RCTs) have attempted to identify therapeutic and interventional strategies that reduce the morbidity and mortality rate in patients that experience perioperative neurological complications. However, there is still no consensus on the best strategy that yields improved patient outcomes, such that standardised neuroprotection protocols do not exist in a significant number of anaesthesia departments. This review aims to discuss contemporary evidence for preventing and managing risk factors for neuronal injury, mechanisms of injury, and neuroprotection interventions that lead to improved patient outcomes. Furthermore, a summary of existing RCTs and large observational studies are examined to determine which strategies are supported by science and which lack definitive evidence. We have established that the overall evidence for pharmacological neuroprotection is weak. Most neuroprotective strategies are based on animal studies, which cannot be fully extrapolated to the human population, and there is still no consensus on the optimal neuroprotective strategies for patients undergoing cardiac surgery. Large multicenter studies using universal standardised neurological fallout definitions are still required to evaluate the beneficial effects of the existing neuroprotective techniques.

Glutamate signalling is an essential aspect of neuronal communication involving many different glutamate receptors, and underlies the processes of memory, learning and synaptic plasticity. Despite neuroinflammatory diseases covering a range of maladies with very different biological causes and pathophysiologies, a central role for dysfunctional glutamate signalling is becoming apparent. This is not just restricted to the well-described role of glutamate in mediating neurodegeneration, but also includes a myriad of other influences that glutamate can exert on the vasculature, as well as immune cell and glial regulation, reflecting the ability of neurons to communicate with these compartments in order to couple their activity with neuronal requirements. Here, we discuss the role of pathophysiological glutamate signalling in neuroinflammatory disease, using both multiple sclerosis and Alzheimer’s disease as examples, and how current steps are being made to harness our growing understanding of these processes in the development of neuroprotective strategies. This review focuses in particular on N-methyl-D-aspartate (NMDA) and 2-amino-3-(3-hydroxy-5-methylisooxazol-4-yl) propionate (AMPA) type ionotropic glutamate receptors, although metabotropic, G-protein-coupled glutamate receptors may also contribute to neuroinflammatory processes. Given the indispensable roles of glutamate-gated ion channels in synaptic communication, means of pharmacologically distinguishing between physiological and pathophysiological actions of glutamate will be discussed that allow deleterious signalling to be inhibited whilst minimising the disturbance of essential neuronal function.

Background and PurposeThe immune response subsequent to an ischemic stroke is a crucial factor in its physiopathology and outcome. It is known that TLR4 is implicated in brain damage and inflammation after stroke and that TLR4 absence induces neutrophil reprogramming toward a protective phenotype in brain ischemia, but the mechanisms remain unknown. We therefore asked how the lack of TLR4 modifies neutrophil function and their contribution to the inflammatory process.MethodsIn order to assess the role of the neutrophilic TLR4 after stroke, mice that do not express TLR4 in myeloid cells (TLR4loxP/Lyz-cre) and its respective controls (TLR4loxP/loxP) were used. Focal cerebral ischemia was induced by occlusion of the middle cerebral artery and infarct size was measured by MRI. A combination of flow cytometry and confocal microscopy was used to assess different neutrophil characteristics (circadian fluctuation, cell surface markers, cell complexity) and functions (apoptosis, microglia engulfment, phagocytosis, NETosis, oxidative burst) in both genotypes.ResultsAs previously demonstrated, mice with TLR4 lacking-neutrophils had smaller infarct volumes than control mice. Our results show that the absence of TLR4 keeps neutrophils in a steady youth status that is dysregulated, at least in part, after an ischemic insult, preventing neutrophils from their normal circadian fluctuation. TLR4-lacking neutrophils showed a higher phagocytic activity in the basal state, they were preferentially engulfed by the microglia after stroke, and they produced less radical oxygen species (ROS) in the first stage of the inflammatory process.ConclusionsTLR4 is specifically involved in neutrophil dynamics under physiological conditions as well as in stroke-induced tissue damage. This research contributes to the idea that TLR4, especially when targeted in specific cell types, is a potential target for neuroprotective strategies.

With the improvement in neonatal rescue technology, the survival rate of critically ill preterm infants has substantially increased; however, the incidence of brain injury and sequelae in surviving preterm infants has concomitantly increased. Although the etiology and pathogenesis of preterm brain injury, and its prevention and treatment have been investigated in recent years, powerful and effective neuroprotective strategies are lacking. Caffeine is an emerging neuroprotective drug, and its benefits have been widely recognized; however, its effects depend on the dose of caffeine administered, the neurodevelopmental stage at the time of administration, and the duration of exposure. The main mechanisms of caffeine involve adenosine receptor antagonism, phosphodiesterase inhibition, calcium ion activation, and γ-aminobutyric acid receptor antagonism. Studies have shown that there are both direct and indirect beneficial effects of caffeine on the immature brain. Accordingly, this article briefly reviews the pharmacological characteristics of caffeine, its mechanism of action in the context of encephalopathy in premature infants, and its use in the neuroprotection of encephalopathy in this patient population.

Abstract Parkinson’s disease (PD) and related neurodegenerative disorders, termed the synucleinopathies, are characterized pathologically by the accumulation of protein aggregates containing α-synuclein (aSyn), resulting in progressive neuronal loss. There is considerable need for the development of neuroprotective strategies to halt or slow disease progression in these disorders. To this end, evaluation of genetic mutations associated with the synucleinopathies has helped to elucidate crucial mechanisms of disease pathogenesis, revealing key roles for lysosomal and mitochondrial dysfunction. The GBA1 gene, which encodes the lysosomal hydrolase β-glucocerebrosidase (GCase) is the most common genetic risk factor for PD and is also linked to other neurodegenerative disorders including dementia with Lewy bodies (DLB). Additionally, homozygous mutations in GBA1 are associated with the rare lysosomal storage disorder, Gaucher’s disease (GD). In this review, we discuss the current knowledge in the field regarding the diverse roles of GCase in neurons and the multifactorial effects of loss of GCase enzymatic activity. Importantly, GCase has been shown to have a bidirectional relationship with aSyn, resulting in a pathogenic feedback loop that can lead to progressive aSyn accumulation. Alterations in GCase activity have furthermore been linked to multiple distinct pathways involved in neurodegeneration, and therefore GCase has emerged as a promising target for therapeutic drug development for PD and related neurodegenerative disorders, particularly DLB.