Foreword

The central nervous system is a kind of information center where neural communications handle and process incoming information from the periphery, make decision and send command back to the periphery to control the whole body. On the other hand, brain neurons are vulnerable to various kinds of insults and have only limited regenerative capacities. Accordingly, damage of brain tissues often results in severe and enduring disabilities. Here we have five review articles under the heading of “Brain Damage and Potential Therapeutic Interventions” that describe current understanding of the pathophysiology of neurodegenerative conditions and potential therapeutic strategies to overcome neurological problems.

Recent decades associated with population aging have seen a prominent increase of patients with neurodegenerative disorders that include Parkinson’s disease (PD). Studies on inherited cases of PD have identified mutants of DJ-1 among other causative gene products. The review by Hijioka et al. explains physiological functions of DJ-1 such as antioxidative properties as well as regulation of gene transcription, protein folding and protein degradation. PD-associated mutation disrupts these functions of DJ-1 and contributes to neurodegenerative events. Hijioka et al. also introduce examples of DJ-1 mimetic and DJ-1 binding compounds that produce beneficial effects on experimental models of Alzheimer’s disease (AD) and ischemic stroke as well as PD.

Oxidative stress plays a critical role in the injury of the central nervous system under pathological conditions. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that acts as a part of defensive mechanisms against oxidative stress, and the review by Kume summarizes accumulating lines of evidence indicating that Nrf2 is a promising drug target. Indeed, several low-molecular-weight compounds exert beneficial effects on experimental models of PD, multiple sclerosis and ischemic stroke. Remarkably, one of these compounds (dimethyl fumarate) has been approved for treatment of multiple sclerosis, which substantiates the validity of Nrf2-directed drug development.

Stroke disorders, which are categorized as either ischemic stroke or hemorrhagic stroke, are the typical acute disorders associated with brain tissue damage. The review by Ikeda-Matsuo provides a comprehensive account for the roles of eicosanoid signaling in ischemic brain injury. Key issues are the roles of microsomal prostaglandin E synthase-1 (mPGES-1) in the production of prostaglandin E₂ (PGE₂), a critical mediator of inflammatory responses in the brain. Importantly, mPGES-1-mediated PGE₂ production may be involved in diverse sets of neurological conditions including AD, PD, epilepsy and brain tumors as well as ischemic stroke, indicating that mPGES-1-selective inhibitors may offer novel strategies for treatment of these disorders.

With regard to brain damage induced by hemorrhagic stroke, the review by Katsuki and Hijioka overviews recent efforts to reveal pathogenic mechanisms and identify therapeutic targets of intracerebral hemorrhage. A particular topic is the injury of the internal capsule, an axonal fiber tract frequently affected by hemorrhagic events. Because the injury of this axonal tract is a critical determinant of the severity of neurological symptoms, therapeutic interventions for intracerebral hemorrhage should be aimed to prevent axonal degeneration. The article proposes that inflammatory reactions initiated by neutrophil infiltration may play a key role in, and serve as a potential therapeutic target for, hemorrhage-induced axonal tract injury.

Disruption of the blood–brain barrier (BBB) allows invasion of blood constituents including cellular components (such as neutrophils) and soluble components into the brain parenchyma. Michinaga and Koyama give an overview on the pathogenic consequences of BBB disruption including brain edema, inflammation and hemorrhage. They also summarize the findings on the roles of key players that affect BBB integrity under pathophysiological conditions. Vascular endothelial growth factors, matrix metalloproteinases and endothelins are the representatives of bioactive molecules involved in BBB disruption and therefore may serve as targets for novel pharmacotherapies, which might be realized in part by drug repositioning.

Diverse sets of cellular and molecular events may trigger, accelerate, prolong or diminish the damage of brain tissues. Review articles in this issue provide excellent summaries on recent topics on brain damage and protection, with special reference to key cellular and molecular components involved in the pathogenic and neuroprotective events. These review articles will aid future advancement of researches on this topic, which enables the establishment of novel and effective pharmacotherapies for brain disorders.