A growing body of evidence has highlighted the role of neuroinflammation in the pathogenesis of many neurological diseases. While neuroinflammation has been well characterised in some conditions, notably multiple sclerosis, it is now known to play a role in diseases that have been considered non-inflammatory, including Alzheimer’s disease, amyotrophic lateral sclerosis, movement disorders, stroke, migraine and epilepsy. Neuroinflammation was the overarching theme of the 5th congress of the European Academy of Neurology (EAN), which took place from 29 June to 2 July 2019 in Oslo, Norway.
In a plenary symposium, Prof. Annamaria Vezzani, from the IRCCS-Mario Negri Institute for Pharmacological Research in Milan, Italy, discussed the role of neuroinflammation in epilepsy. The development of epilepsy is associated with an increased and persistent inflammatory state in the microenvironment of neural tissue.1 This may originate in the central nervous system (CNS) or be acquired from systemic circulation due to a breakdown of the blood–brain barrier (BBB). Within the CNS, glial cells produce pro-inflammatory cytokines such as interleukin 1-beta. These promote the release of glutamate from astrocytes and decrease the re-uptake of glutamate, increasing glutamate availability in neuronal synapses and promoting neuronal hyper-excitability.1
A number of pathways, including the IL-1 receptor-Toll-like receptor 4 axis, arachidonic acid-prostaglandin cascade and transforming growth factor-β signalling associated with BBB dysfunction, have been found to be activated in patients with refractory epilepsy. Studies in animal models have targeted these pathways and have reported beneficial effects in terms of seizure frequency, neuronal cell loss and neurological comorbidities.1 Targeting oxidative stress is another potentially useful strategy; the use of antioxidant drugs such as N-acetylcysteine and sulforaphane has been found to reduce seizure frequency in animal models of epilepsy.2 In other studies, anti-inflammatory and antioxidant drugs have been administered to rodents during status epilepticus. Results have shown a reduction in cognitive deficits and seizure progression in animals developing epilepsy.3 Therefore, controlling inflammation in such disorders may reduce the risk of developing epilepsy.
The theme of the next presentation, which was given by Prof. Vidar Gundersen of the University of Oslo, Norway, was neuroinflammation in Parkinson’s disease (PD). The diagnosis of PD is largely based on the assessment of motor symptoms that present only when a substantial portion of the dopaminergic neurons in the substantia nigra pars compacta have already degenerated.4 The misfolded protein α-synuclein, which becomes insoluble and forms aggregates within the neuronal Lewy bodies, leading to neuronal death, is a characteristic biological feature of PD.5 Studies of foetal grafts have shown that activated microglia are present long before the accumulation of α-synuclein pathology in implanted dopamine neurons. This suggests that microglial activation contributes to the development of α-synuclein pathology.6 Microglial activation has also been demonstrated in patients with PD, using positron emission tomography (PET).7 Elevated levels of cytokines including interleukin 1-beta, have been detected in the blood and cerebrospinal fluid of PD patients with PD.8
Prof. Gundersen also discussed the gut hypothesis, which postulates that PD pathology starts in the gastrointestinal tract then spreads through the vagus nerve to the brain.9 This has led to the suggestion that antidiabetic drugs that affect the gut–brain axis could be used in the treatment of neurodegenerative diseases. In a clinical trial, exenatide, a glucagon-like peptide-1 agonist, improved motor and cognitive functions in patients with PD,10 and several other studies are ongoing.
Prof. Guido Stoll from the University of Würzburg, Germany, described the role of T cells in ischaemic stroke. It is known that ischaemic reperfusion injury occurs in some patients after recanalisation.11 The mechanism underlying this process is the interaction of T cells with platelets, facilitating further infarct development through a complex process known as thrombo-inflammation, which involves the CD84 receptor.12 Although the immune system has not been traditionally considered as a therapeutic target in stroke, a number of studies have investigated anti-inflammatory therapies, such as natalizumab and fingolimod, in patients with acute stroke.13 In a phase II study, natalizumab failed to meet the primary endpoint of reductions in focal infarct volume growth, but was associated with improved clinical outcomes over 90 days, compared with placebo.14 The findings suggested a more diffuse process of post-ischaemic inflammation, rather than one focused at the infarct location, and will form the basis of future clinical trials.
Finally, Prof. Lars Edvinsson from Lund University, Sweden, described his work on the role of inflammation in migraine. Monoclonal antibody antagonists of the calcitonin gene-related peptide (CGRP) and its receptor, and recently approved monoclonal antibody therapies, such as fremanezumab, galcanezumab, eptinezumab, and erenumab, have been the most exciting recent development in migraine treatment. Although many CGRP receptors are located within the brain, these therapies do not cross the BBB, and appear to target the trigeminal ganglion.15 Previous studies have suggested that inflammation within the dura was involved in the pathogenesis of chronic migraines.16 However, Prof. Lars Edvinsson’s team have found no evidence for dural inflammation, and suggest that the mechanism underlying chronic migraine is neurogenic neuroinflammation, possibly due to increased expression of cytokines through activation of protein kinases in neurons and glial cells of the trigeminovascular system.17
These studies have highlighted our growing understanding of the vital role of neuroinflammation in neurological diseases. This should increase provide new insights into causes of these diseases and help to identify novel therapeutic targets, with the ultimate goals of modifying disease processes and optimising patient outcomes.
References
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