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Prof. Hideki Hara, Ph.D., R.Ph., Molecular Pharmacology, Gifu Pharmaceutical University
1983 Pharmacist, Bachelor of Science, Department of Pharmacology, Gifu Pharmaceutical
University
1983-1999 Kenebo Ltd., Pharmaceutical Research Center
1988-1991 Research Scientist, Department of Neurology, Institute of Brain Diseases, Tohoku
University School of Medicine
1994-1996 Postdoctoral Fellow, Neuroscience Center (Neurology and Neurosurgery),
Massachusetts General Hospital, Harvard Medical School, MA, USA
1999-2004 General Manger, Ophthalmic Research Center, Santen Pharmaceutical Ltd.
2004-present Professor, Gifu Pharmaceutical University
2008-2010 Research Director of Molecular Imaging, Institute of Physical and Chemical Research
(RIKEN)
2009-present Department Chairman, Gifu Pharmaceutical University
Research fields: Pharmacology, Neurology, Ophthalmology, Molecular Imaging
Brain imaging in laser-induced ocular hypertensive monkeys using PET and MRI
Hideaki Hara
Molecular Pharmacology, Department of Biofunctional Evaluation,
Gifu Pharmaceutical University
Open-angle glaucoma (OAG) is a slowly progressive and irreversible ocular disease that is a leading
cause of blindness. Therefore, evaluation of the appearance of the optic nerve head and peripapillary
retina were paying attention to diagnose OAG, especially in its early stage. Glaucoma pathology has
been extensively studied at the level of the retinal ganglion cells (RGC) and optic nerve (ON).
Measurements of intraocular pressure (IOP), ophthalmoscopy, and visual field have been mainly
employed for the diagnosis of OAG.
Recently, it has been reported that the RGC death is accompanied by transsynaptic degradation
of neurons in the lateral geniculate nucleus (LGN), which is the primary processing center for visual
information received from the retina, in glaucoma patients. In experimental glaucoma monkeys, it
was suggested that neuronal atrophy in LGN may occur in the early stage after IOP elevation, and
that LGN neurons may be more susceptible to the effects of IOP elevation than ON axons.
Furthermore, it has been reported that in chronic hypertensive rats microglial activation is observed
in both sides of the LGN during the early phase, at 1 week after IOP elevation, and this is most
significant at 1 and 2 months.
However, the pathophysiological process of LGN degeneration in glaucoma is as yet unknown.
Here, we examined a possible early diagnosis of glaucoma on the basis of the LGN and ON
degenerations in experimental glaucoma monkeys using a positron emission tomography (PET) and
magnetic resonance imaging (MRI), respectively, and validated their changes by immunohistological
examinations. Glial cell activation was detected by PET imaging with [11C]PK11195, a PET ligand
for peripheral-type benzodiazepine receptor (PBR), and [11C]PK11195 binding potential was
increased in the bilateral LGN at 4 weeks after IOP elevation. Diffusion MRI also showed the
decreased density of ON axons at 4 weeks after IOP elevation.
The present findings suggest that pathological changes occur in LGN and ON at an early
glaucoma stage, and noninvasive molecular imaging in LGN and ON may be useful for early
diagnosis of glaucoma.
CURRICULUMVITAE
Hirokazu Hara, PhD
Associate Professor
Laboratory of Clinical Pharmaceutics
Gifu Pharmaceutical University
Education:
BS, Gifu Pharmaceutical University, 1989.
Ph.D., Molecular biology, Gifu Pharmaceutical University, 1994.
Professional background:
1994-1998 Research Scientist, Shionogi Research Laboratories, Shionogi &
Co., Ltd.
1998-2002 Instructor, Gifu Pharmaceutical University
2002-2003 Research Associate, Department of Neurobiology, University of
Pittsburgh School of Medicine
2005- 2006 Assistant Professor, Gifu Pharmaceutical University
2006- present Associate Professor, Gifu Pharmaceutical University
Research field:
Neurochemistry, Molecular biology
Molecular basis of compounds with neuroprotective effects
against oxidative stress
Hirokazu Hara
Laboratory of Clinical Pharmaceutics, Gifu Pharmaceutical University
Under physiological conditions, cells maintain redox balance through
generation and elimination of reactive oxygen species (ROS), including superoxide
and hydrogen peroxide. However, an increase in ROS production or a decrease in
ROS-scavenging capacity due to exogenous stimuli or endogenous metabolic
alterations can disrupt redox homeostasis, resulting in oxidative stress. Many
studies suggest that oxidative stress is related to the central nervous system (CNS)
disorders, such as ischemic stroke, Alzheimer’s disease and Parkinson’s disease.
1. Neuroprotective compounds with preconditioning effects: Exposure of cells to
sub-lethal stresses provides adaptation to subsequently more severe stresses. This
phenomenon is referred to as preconditioning. Transient cerebral ischemia and
some pharmacological drugs have been shown to trigger preconditioning against
oxidative stress in neurons. Since these stimuli induce expression of antioxidant
genes such as heme oxygenase-1 (HO-1), acquisition of resistance to oxidative stress
in neurons is thought to contribute to the preconditioning. We have found that
apomorphine, an anti-Parkinsonian drug, and thapsigargin, an endoplasmic
reticulum stress inducer, elicit preconditioning against oxidative stress-induced
neurotoxicity and induce HO-1 expression. Here, I will discuss the mechanism by
which these agents confer adaptation to oxidative stress.
2. Chalcone glycosides with inhibitory effects on NO production in microglia:
Microglia, resident immune cells in the CNS, are activated in response to neuronal
injury. Activated microglia produce nitric oxide (NO) and superoxide, resulting in
formation of the highly toxic product, peroxynitrite. Since NO and its metabolites
cause neuronal cell death, suppression of NO production in microglia is thought to
lead to neuronal protection. We have found that chalcone glycosides isolated from
Brassica rapa L. ‘hidabeni’ prevent lipopolysaccharide-induced NO production via
inhibition of STAT1 activation.
Our findings suggest that these compounds might be good candidates for the
development of novel neuroprotective drugs.