Recently published data from the Centers for Disease Control (CDC) indicated that cerebrovascular disease was the fourth leading cause of death. This fact reminds us that diseases of the nervous system continue to pose both a diagnostic as well as treatment challenge. As such, further research is warranted in order to shed light on the latest understanding in the diagnosis and pathophysiology of neurological disease. In an attempt to increase our focus on the research, we have selected 12 representative articles among numerous submissions for discussion at the Tiantan International Stroke Conference in 2012, one of the largest stroke conferences in the world. This current special issue of Neurological Research will primarily deal with cerebrovascular disease, especially stroke. Another prominent neurologic disease, amytrophic lateral sclerosis (ALS) will be featured along with additional articles concerning traumatic brain injury (TBI) and neuropathic pain.
As more and more research is conducted in cerebrovascular disease, more attention is being directed to systems seemingly outside of the realm of the nervous system. This notion is echoed by a featured article in which the authors advocate a more comprehensive approach. Research should no longer primarily focus on the neuron, but be directed towards the neurovascular unit, which also encompasses glial and vascular elements. Understanding the complex interplay between the three will be critical in identifying potential therapeutic avenues for cerebrovascular disease.
Although looking ‘outside’ the nervous system is an important step in better understanding the mechanisms behind neuroprotection, other authors are advocating looking outside the ischemic penumbra for clues towards neuroprotection in a post-stroke setting. Past research in stroke has primarily focused on possible therapies within the ischemic penumbra. This issue of Neurological Research features an article in which the authors assert that attention should be shifted to possible remedies directed beyond the ischemic penumbra. Reasons for this are twofold. First, damage within the ischemic penumbra often occurs so rapidly that any attempts for treatment often prove futile. Second, there is increasing evidence that stroke induces numerous cellular and hemodynamic changes outside the region of ischemia. As such, the pathophysiological cascades that occur in non-ischemic brain tissue warrant further investigation as it could hold the key to post-stroke neuroprotection.
The current issue highlights many novel notions of stroke pathophysiology, knowledge of which could spur future treatment. NADPH oxidase (NOX) was originally identified in neutrophils as serving a critical role in the immune system as an antibacterial. Recent research has elucidated that while NOX may play a beneficial role in the immune system that it may be deleterious in stroke. In fact, the same properties — the ability to generate free radicals — that make NOX such an effective antimicrobial, appear also to cause damage in a stroke setting. The superoxide generated by NOX is thought to contribute to blood–brain barrier disruption, edema formation along with secondary hemorrhage. NOX is thought to mediate most of its damage in the post-stroke period in which blood flow, and thus, oxygenation is re-established. The reintroduced oxygen thus serves as a substrate for NOX, which leads to superoxide production and the aforementioned sequelae. Subsequently, blocking NOX, especially in the re-oxygenation phase, could attenuate many of the negative outcomes seen in stroke.
While carotid artery atherosclerosis remains a major causative agent in stroke, such a condition typically affects an older population. Little in the existing literature addresses risk factors in younger stroke victims. Although most do not view stroke in the young as a pressing issue, this is not the case in China. An estimated 10% of stroke cases in China are in those aged 18–45 years and with some epidemiological studies indicating stroke as the leading cause of death in China, stroke in the young thus represents a significant if not overlooked issue. This current issue reveals several potential risk factors for stroke unique to a younger population such as pregnancy as well as oral contraceptive use. The authors also identified patent foramen ovale and hereditary diseases such as Fabry’s disease and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencepalopathy (CADSIL) as additional risk factors for stroke in the young. Although many risk factors were posited, the authors noted that one of the most common causes of stroke in the young was due to spontaneous arterial dissection, a condition with few if any risk factors. Thus, while risk factor identification remains an important tool in identifying potential stroke patients, research focusing on the pathological processes in stroke remains paramount in decreasing stroke’s morbidity and mortality.
Carotid artery atherosclerosis has long been recognized as a risk factor for transient ischemic attacks along with stroke. Research in the current issue aims to expand our knowledge of carotid artery atherosclerosis by examining the relation between plaque composition and stenosis patterns. Numerous plaque compositions have been identified, including intraplaque hemorrhage, lipid-necrotic core, ulcerative plaque, and calcified plaque. Intraplaque hemorrhage was more likely to be associated with a complete carotid blockage, while a lipid-necrotic core was more likely to be found in a stenosis pattern without distal flow compromise.
The idea of neuroprotection, specifically pituitary adenylate cyclase activating polypeptide (PACAP)-mediated neuroprotection is also covered in this special edition. Prior literature has established PACAP-induced neuroprotection; however, the exact mechanism has remained illusive. The authors suggest that Toll-like receptors may play a role in this neuroprotection suggesting an immune basis in neuroprotection. It was found that pre-treatment with PACAP to in vitro microglial cells prior to oxygen-glucose depravation/reoxygention leads to less hypoxic injury on a basis of inhibiting upregulation of Toll-like receptor 4. Toll-like receptor-4 is a key regulator in the innate immune and inflammatory response systems. While microglia in many ways represent the immune system of the central nervous system, the fact that Toll-like receptors could play a role in neuroprotection represents somewhat of a novel idea.
Even though stroke remains the primary focus of this special edition of Neurological Research, attention is also given to other pathologies of the nervous system, namely, TBI and ALS. TBI represents a major public health concern and yet scant advances in TBI treatment has been made within the past 30 years. Central to this issue is a lack of understanding in the pathological processes induced by brain trauma. Work featured in this issue identifies GSK-3beta, a serine/threonine kinase, as a pivotal component of the apoptotic processes seen after TBI. It was shown that in the face of TBI, GSK-3beta was inactivated, contributing to neuronal death. Other work in this issue reveals that GSK-3beta is not just limited to trauma but extends to neurodegenerative diseases such as ALS. Mice with ALS were shown to display higher levels of phosphorylated GSK-3beta, further indicating the important role GSK-3beta has in neuroprotection.
Focusing on stroke diagnosis, management, and mechanisms, this special edition of Neurological Research presents studies designed to improve the clinical decision making of ischemic or hemorrhagic stroke patients, especially in the Chinese population. Through greater understanding of the underlying mechanisms and novel treatment options for stroke, we will continue to garner momentum in the fight against cerebrovascular disease.
As we reflect on this special issue, we must acknowledge Dr Ben Roitberg, the editor-in-chief, for his great effort and support in preparation of this issue.