Foreword

The central nervous system (CNS) consists of the nerves in the brain and spinal cord; these are protected within the skull and vertebral canal of the spine, respectively. The network of neurons in the brain processes information sent from the peripheral nervous system, and sends back signals that allow us to respond to changes in the external environment. The neuronal network is composed of approximately 100 billion neurons and synapses, and requires efficient electrical signaling to process information. An increase in the number of neurons in the cortex is positively associated with folding of the cerebral cortex, which contributes to the development of higher brain function.¹⁾ There is no doubt that the development of brain structure and function is influenced by the microenvironment of the brain, where many humoral factors are involved in the production of the cortical folds.²⁾ The transport of nutrients and other substances into the CNS, and the elimination of metabolites and toxins, are tightly controlled by the blood–brain and blood–cerebrospinal fluid barriers. The membranes of cells that serve as the interface between the extra- and intra-cellular spaces play essential roles in both information transmission and microenvironmental homeostasis. Functionally, these tasks are mediated by the interactions of membrane proteins, such as receptors, channels and transporters, with various humoral factors in brain interstitial fluid. Accordingly, an understanding of the expression levels and functional activities of these membrane proteins is essential in order to understand brain function.

During the 39th Symposium on Biological Membranes and Drug Interactions held at Kanazawa in October 2017, with financial support from the Pharmaceutical Society of Japan, the mini-symposium 2 focused on the “Function of Biological Membranes that Regulate the CNS.” This provided a venue for pharmaceutical scientists, pharmacologists and physiologists to summarize and update information on a wide range of topics related to biological membranes, especially transient receptor potential (TRP) channels, prostaglandin E (EP) receptors, and glutamate transporters, from the viewpoint of developing therapeutics for refractory brain diseases. Here, we briefly introduce three reviews of selected topics in the symposium: 1) The molecular mechanism of cortical folding in the ferret, by Dr. Kawasaki, 2) Carrier-mediated transport of nicotine across the blood–brain barrier and its interaction with CNS drugs, by Dr. Hosoya and colleagues, and 3) The diverse role of prostaglandin carriers in neuro-inflammation and fever generation, by Dr. Nakanishi and colleagues.

Kawasaki, who discovered that fibroblast growth factor (FGF) signaling preferentially increases layer 2/3 neurons and generates the protrusion of cortical gyri,¹⁾ reviewed the successful reproduction of cortical folding in the brain using in utero electroporation techniques in ferret models. This rapid and efficient genetic manipulation approach represents an important strategy for neuroscience research in higher mammals in order to understand not only the development of the brain, but also brain disorders.

Hosoya and colleagues reviewed evidence that the permeation of nicotine through the blood–brain and inner blood–retina barriers is mediated by the same H⁺/organic cation antiporter.^3,4) Their work will help us to better understand smoking–drug interactions in the CNS, which will be useful in the development of safer and more effective non-smoking therapies.

Nakanishi and colleagues have recently shown that organic anion transporting polypeptide (Oatp) 2a1/Slco2a1 significantly influences the local concentration of prostaglandin E₂ (PGE₂) and the progression of inflammation⁵⁾; this is noteworthy, since more than a dozen transporters mediate PGE₂ transport across the plasma membrane in mammals. The authors reviewed carriers associated with prostaglandin transport in the brain, summarizing current evidence on their expression levels and functions. This will be helpful to understand potential mechanisms involved in neuro-inflammation and brain diseases.

The reviews introduced here confirm that the barrier function of the brain, as well as changes in the brain microenvironment, greatly affect higher brain function and the onset of brain disease. Nevertheless, molecular studies of the relationship of biological membranes to higher functions of the brain are still at an early stage. These reviews should be of interest to readers of the Biological and Pharmaceutical Bulletin, and are expected to contribute to the progress of research in this field and to the development of new CNS drugs.

References

• 1) Sun T, Hevner RF. Growth and folding of the mammalian cerebral cortex: from molecules to malformations. Nat. Rev. Neurosci., 15, 217–232 (2014).
• 2) Masuda K, Toda T, Shinmyo Y, Ebisu H, Hoshiba Y, Wakimoto M, Ichikawa Y, Kawasaki H. Pathophysiological analyses of cortical malformation using gyrencephalic mammals. Sci. Rep., 5, 15370 (2015).
• 3) Tega Y, Akanuma S, Kubo Y, Terasaki T, Hosoya K. Blood-to-brain influx transport of nicotine at the rat blood–brain barrier: involvement of a pyrilamine-sensitive organic cation transport process. Neurochem. Int., 62, 173–181 (2013).
• 4) Tega Y, Kubo Y, Yuzurihara C, Akanuma S, Hosoya K. Carrier-mediated transport of nicotine across the inner blood–retinal barrier: Involvement of a novel organic cation transporter driven by an outward H(+) gradient. J. Pharm. Sci., 104, 3069–3075 (2015).
• 5) Nakanishi T, Hasegawa Y, Mimura R, Wakayama T, Uetoko Y, Komori H, Akanuma S, Hosoya K, Tamai I. Prostaglandin transporter (PGT/SLCO2A1) protects the lung from bleomycin-induced fibrosis. PLOS ONE, 10, e0123895 (2015).