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Tanaka. Neuroimmunol Neuroinflammation 2020;7:73-91 I http://dx.doi.org/10.20517/2347-8659.2020.04 Page 85

Noradrenaline and other cAMP-elevating agents
As shown in Figure 3, noradrenaline (NA) and related agents have significant inhibitory effects on
activated microglia. These effects have been attributed mainly to the adrenergic β2 receptor that
increases levels of intracellular cAMP [73,88] . The β2 agonist terbutaline strongly suppressed LPS-induced
proinflammatory activation of microglia. cAMP-elevating agents, such as phosphodiesterase (PDE)
[89]
inhibitors also exhibited strong inhibitory effects on LPS-treated microglia . Rolipram, an inhibitor of
the cAMP-selective hydrolase PDE4, may be the PDE inhibitor with the strongest inhibitory effects on rat
primary microglia. A cAMP-analogue, 8-bromo cAMP, and forskolin, an activator for adenylate cyclase,
also have strong inhibitory effects on microglia in vitro. Furthermore, the cAMP-elevating agents inhibit
[90]
proliferation of microglia in vitro . However, it should be noted that adrenergic a1 receptor agonists
such as phenylephrine can inhibit microglial activation to an extent similar to that of terbutaline [73,88] .
[73]
The inhibitory effects of NA cannot be eliminated by an inhibitor for cAMP-dependent protein kinase .
[73]
NA, a1, and β2 agonists strongly prevent LPS-induced translocation into the nuclei of NFkB . This
effect is mediated mainly by suppression of IkB degradation. NA and the agonists suppressed LPS-
induced phosphorylation of STAT1 and expression of IRF1. IRF1 may contribute significantly to microglia
activation . However, the precise molecular mechanisms underlying the inhibitory effects of NA, in
[43]
addition to the agonists, remain to be identified.

These studies may indicate that BBB-permeable adrenergic agonists are promising agents for suppressing
neuroinflammatory processes in pathologic brains. The curative effects of BBB-permeable β2 agonists,
while preventing the proinflammatory nature of microglia in the SNc, have been shown in murine PD
models . In AD pathology, NA neurons in the locus ceruleus, which is the most important NA source
[91]
in the brain, undergo degeneration leading to microglia activation. This subsequently results in further
neuronal degeneration . However, there are many conflicting studies demonstrating the stimulatory
[92]
[93]
actions of NA and the adrenergic agonists on microglia in the brain .
TGFβ1
TGFβ1 may be the most abundantly released cytokine from microglia and macrophages in severely damaged
brains [27,72] . TGFβ1 suppresses iNOS expression by LPS-treated primary rat microglia almost completely
in culture at both mRNA and protein levels. The inhibitory effect of TGFβ1 is as strong as is 100 nM
[72]
of Dex in culture experiments . As mentioned above, once incubated with TGFβ1, LPS cannot induce
NFkB translocation into nuclei in microglia. TGFβ1 also inhibits LPS-induced phosphorylation of STAT1
and expression of IRF1. Although TGFβ1 does not increase expression of the M2 markers CD206 and
Ym1, it increases expression of the neuroprotective factors HGF and bFGF. When TGFβ1 was injected into
ischemic tissues 48 h after MCAO, the immunoreactivity of pIKK in the tissue surrounding the injection
site was suppressed markedly in a dose-dependent manner.

Severely damaged brain tissues contain DAMPs that should induce proinflammatory activation of
microglia and macrophages. DAMPs bind to TLRs on both microglia and macrophages, resulting in
translocation of NFkB into nuclei. Microglia and macrophages should then display proinflammatory
phenotypes expressing proinflammatory mediators. However, there were very few pIKK-bearing or
iNOS-expressing microglia/macrophages in the lesion, especially during the subacute phase when TGFβ1
expression is high. Interventions to increase the actions of TGFβ1 for stroke models have been shown to
[94]
ameliorate the outcomes for severely damaged brains . Thus, TGFβ1 may ameliorate severe CNS damage
through inducing anti-inflammatory phenotypes of microglia and macrophages.

Bromovalerylurea
Bromovalerylurea (BU; C H BrN O , CAS: 496-67-3) is a hypnotic/sedative that was developed more than
2
6
11
2
[95]
a century ago . It is not prescribed currently because of its weak actions as a hypnotic/sedative compared