11月20日担当の薬理学講座の川村です。
以下の論文を紹介いたします。
Yuri Hirayama, Ha Pham Ngoc Le, Hirofumi Hashimoto, Itsuko Ishii,
Schuichi Koizumi and Naohiko Anzai
eNeuro 11 April 2024, 11 (4) ENEURO.0494-23.2024;
Abstract
A sublethal ischemic episode [termed preconditioning (PC)] protects
neurons in the brain against a subsequent severe ischemic injury. This
phenomenon is known as brain ischemic tolerance and has received much
attention from researchers because of its robust neuroprotective
effects. We have previously reported that PC activates astrocytes and
subsequently upregulates P2X7 receptors, thereby leading to ischemic
tolerance. However, the downstream signals of P2X7 receptors that are
responsible for PC-induced ischemic tolerance remain unknown. Here, we
show that PC-induced P2X7 receptor-mediated lactate release from
astrocytes has an indispensable role in this event. Using a transient
focal cerebral ischemia model caused by middle cerebral artery
occlusion, extracellular lactate levels during severe ischemia were
significantly increased in mice who experienced PC; this increase was
dependent on P2X7 receptors. In addition, the intracerebroventricular
injection of lactate protected against cerebral ischemic injury. In in
vitro experiments, although stimulation of astrocytes with the P2X7
receptor agonist BzATP had no effect on the protein levels of
monocarboxylate transporter (MCT) 1 and MCT4 (which are responsible for
lactate release from astrocytes), BzATP induced the plasma membrane
translocation of these MCTs via their chaperone CD147. Importantly,
CD147 was increased in activated astrocytes after PC, and CD147-blocking
antibody abolished the PC-induced facilitation of astrocytic lactate
release and ischemic tolerance. Taken together, our findings suggest
that astrocytes induce ischemic tolerance via P2X7 receptor-mediated
lactate release.
Significance Statement
Brain ischemic tolerance refers to an endogenous neuroprotective
phenomenon whereby a nonlethal ischemic episode, termed preconditioning
(PC), induces resistance to a subsequent severe ischemic injury. This
phenomenon has received much attention because of its robust
neuroprotective effects. We have previously reported that the PC-evoked
activation of astrocytes leads to ischemic tolerance; however, the
underlying molecular mechanisms remain unknown. Here, we have
demonstrated that PC induces the membrane translocation of lactate
transporters in activated astrocytes, thereby promoting lactate release
from astrocytes during severe ischemia; this effect likely plays a role
in ischemic tolerance. These findings may facilitate the development of
new therapeutic strategies for cerebral ischemia.
何卒よろしくお願いいたします。
薬理学講座 川村将仁
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Masahito Kawamura Jr. m.kawamura@jikei.ac.jp
Department of Pharmacology
Jikei University School of Medicine
3-25-8 Nishi-shimbashi, Minato,
Tokyo 105-8461, Japan