**1. Introduction of atmospheric plasma for medical application**

Medical applications of atmospheric plasma have been intensively studied [1]. These studies have reported numerous applications, such as for sterilization [2, 3], decomposition of harmful substances [4]andsurfacetreatments [5–7].Inrecentyears,thisareaofresearchhasbeenfocused on the practical utilization of atmospheric plasma in the medical filed, such as for blood coagulation [8, 9], wound healing [10–12] and cancer treatment [13–15]. On the other hand, dermatology is one area ofmedicine where atmosphericplasma applications are currentlyused in practice [16], such as in a device to treat acne or wrinkles [17] and to treat stretch marks in combination with ultrasonic waves [18, 19]. As explained above, various research and development efforts have been conducted in the application of plasma medicine; however, we do not yet know whether plasma irradiation can be used to treat various symptoms. Though, the basic

mechanisms of cell response [13–15] and the bacterial sterilization process [2, 3] have been studied intensively, effectiveness of plasma medicine in treating depression, which is a social problem in contemporary countries such as Japan, and Alzheimer's disease, which is an increasingprobleminagingsocieties,hasnot stillbeeninvestigated.Theuseofplasmamedicine to treat various otherdiseases, such as cerebral infarction andhigh bloodpressure, also requires additional investigation. Reactive oxygen species (ROSs) and reactive nitrogen species (RNSs) couldplay importantroles inthe beneficial effects ofplasmamedicine.Mechanismsunderlying these effects could be quite complicated because of the physiological activation in the body by ROS signalling [20]. Fundamental research to elucidate the cellular response is currently under investigation. In contrast, reactive species generated in plasma or exposed liquid medium have demonstratedefficacy fortreating various cancers, butnotforthepreviouslymentionedmental disorders, other associated symptoms or diseases such as diabetes, cerebral infarction and high blood pressure [21]. Fortunately, mechanisms of depression and Alzheimer's disease have been revealed in detail. The inhibited production of neurotransmitters (serotonin, noradrenalin and dopamine) causes depression, and Alzheimer's disease occurs because of the deposition of a peptide called amyloid-ß on the cerebral cortex. Research and development of effective drugs fortreatingmentaldisordersareproceeding[22].Thesedrugsareadministratedorally;however, the effects of many of these drugs are delayed because of absorption in the small intestine. Moreover, as is the case with oral administration, absorption of drugs in additional locations is different for each person. Thus, administration by injection is used if a precise or high dose of drugs is needed [23, 24]. Administration of poorly absorbed drugs is also the same. However, frequent injections are not desirable in the view of a patient's quality of life (QOL). We can point out the following questions to guide the future of plasma medicine and develop it into a strong tool for the treatment of various symptoms:


As mentioned in many of the references, recent studies of plasma medicine are mostly focused on direct or indirect actions of the active species. Hence, clinical cases, such as Alzheimer's disease, diabetes, cerebral infarction and high blood pressure, have not yet been investigated to determine whether reactive species and plasma medicine could be an effective treatment. Applying plasma medicine for treatment of various symptoms, we have been considering plasma irradiation as a method to deliver appropriate drugs [25]. One instance of this use is the enhancement of percutaneous absorption by atmospheric microplasma irradiation. Percutaneous absorption is a drug administration method in which drugs are absorbed into the skin or body. In this sense, this method is similar to an injection; however, there is no need for a needle in plasma irradiation. Administering drugs in ways that do not require needles could increase patient QOL and reduce the rate of infections. In addition, percutaneous absorption has several advantages, such as preventing metabolism of the drug [24] and stabilizing the concentration of drug in the blood [26]. However, it has disadvantages as well, such as the limitation of the molecular weight of the drug [27] and the need for moderate

solubility of the drug in lipids [28]. The stratum corneum layer inhibits drug penetration because the skin acts as a barrier to guard our body from foreign substances.
