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Page 86 Tanaka. Neuroimmunol Neuroinflammation 2020;7:73-91 I http://dx.doi.org/10.20517/2347-8659.2020.04

with newer agents such as benzodiazepines and also due to dependency. Recently, it has been found to have
strong anti-inflammatory effects [10,43,96,97] . The effects of BU on LPS-treated primary rat microglia are as
[43]
strong as those of Dex . Like Dex, BU increases the expression of neuroprotective factors such as HGF or
IGF-1 by LPS-treated primary microglia while inhibiting the expression both of proinflammatory factors
and of the proinflammatory transcription factors IRF1, IRF7, and IRF8 [43,98] . Although BU does not suppress
LPS-induced NFkB translocation into nuclei, its inhibitory effects are exerted at the transcriptional level.
BU inhibited ATP synthesis in mitochondria; this may be related to its anti-inflammatory effects [10,96] .
Moreover, BU inhibits Janus kinase 1 activity, thus suppressing the phosphorylation of STAT1 and the
[43]
subsequent expression of IRF1 .

BU prevented the death of rats with cecum ligation and puncture-induced sepsis by suppressing the
[97]
proinflammatory activation of peritoneal macrophages . Oral administration of BU ameliorated PD in rat
[43]
models while inhibiting the expression of proinflammatory mediators in the ventral midbrain . When BU
is added to the LPS-treated microglia/neuron coculture, it can almost completely inhibit neuronal death by
almost completely suppressing the release of NO. In rat TBI models, BU ameliorated neurological deficits
considerably while inhibiting expression of chemokine CCL2 and suppressed monocyte infiltration of the
[10]
lesion . Furthermore, BU inhibited mitochondrial ROS release by macrophages strongly. On the other
hand, BU did not affect the accumulatio of favorable macrophages at later time points.

As BU is a hypnotic/sedative, it crosses the BBB easily. It may hold promise as an agent for ameliorating a
range of brain diseases and injuries. However, BU is associated with marked dependency, and it has been
used for suicide. Nevertheless, recent research has shown that the sleep-inducing effects of BU necessitate
a higher dose than that required to produce the anti-inflammatory effects. As a hypnotic, BU increases the
total sleeping period while reducing rapid eye movement sleep at a dose of 250 mg/kg for rats (Takeda et al.,
unpublished observation). Conversely, BU has been administered to sepsis, TBI, and PD model rats at a
dose of 50 mg/kg. The findings suggest that BU could be used as a specific anti-inflammatory drug without
significant dependency.

Agents that elevate expression of antiapoptotic factors in neurons
Microglia and macrophages can be activated by the presence of damaged neurons because of released
DAMPs. Moreover, damaged neurons will reduce the activity of flippase, which is required for asymmetric
distribution of phospholipids. Flippase reverses the translocation of PS to the exoplasmic face of the plasma
membrane in an ATP-dependent manner. Therefore, even weak neuron damage that reduces intracellular
ATP results in translocation of PS to the exoplasmic surface of the plasma membrane. The PS will be
[99]
recognized by proteins such as MFG-E8 and also by complement C1 . These changes stimulate phagocytic
[66]
elimination of neurons by microglia and macrophages in a process called phagoptosis . Therefore, either
suppression of the apoptotic changes or mitochondrial damage will suppress the unfavorable activation of
microglia and macrophages [100,101] .

A hematopoietic cytokine IL-3 has been shown to increase Bcl-xL expression in neurons in ischemic
[44]
[102]
[103]
hippocampi and in the SNc of PD model rats . Moreover, GM-CSF also increases Bcl-xL expression .
Simultaneous administration of IL-3 and GM-CSF shows more marked ameliorative effects in TBI and PD
model rats. The mixture of the cytokines also inhibited neuronal loss in a rat stroke model prepared by
MCAO. Subcutaneous administration of the cytokine mixture to PD model rats inhibited IL-1β and TNFa
expression in the ventral midbrain, whereas the expression of IGF-1 and HGF was increased. The favorable
changes in microglia may be mediated by the ameliorated survival of neurons. The cytokines also have
specific direct effects on microglia and macrophages [13,104] . Addition of cytokines to the culture of isolated
macrophages (BINCs) from TBI lesions increased HGF and IGF-1 expression, whereas it did not affect IL-
[13]
1β expression . This indicates that inhibition of the proinflammatory nature of the cytokines may be