Publications by authors named "Keith Tatsukawa"

5 Publications

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NPT520-34 improves neuropathology and motor deficits in a transgenic mouse model of Parkinson's disease.

Brain 2021 Jun 12. Epub 2021 Jun 12.

Neuropore Therapies, Inc., 10835 Road to the Cure, Suite 230, San Diego, CA 92121 USA.

NPT520-34 is a clinical-stage, small molecule being developed for the treatment of Parkinson's disease and other neurodegenerative disorders. The therapeutic potential of NPT520-34 was first suggested by findings from cell-based assays of alpha-synuclein (ASYN) clearance. As reported here, NPT520-34 was subsequently evaluated for therapeutically relevant actions in a transgenic animal model of Parkinson's disease that overexpresses human ASYN and in an acute lipopolysaccharide (LPS)-challenge model using wild-type mice. Daily administration of NPT520-34 to mThy1-ASYN (Line 61) transgenic mice for one or three months resulted in reduced ASYN pathology, reduced expression of markers of neuroinflammation, and improvements in multiple indices of motor function. In an LPS-challenge model using wild-type mice, a single-dose of NPT520-34 reduced LPS-evoked increases in the expression of several pro-inflammatory cytokines in plasma. These findings demonstrate the beneficial effects of NPT520-34 on both inflammation and protein-pathology endpoints, with consequent improvements in motor function in an animal model of Parkinson's disease. These findings further suggest that NPT520-34 may have two complementary actions: (1) to increase the clearance of neurotoxic protein aggregates and (2) to directly attenuate inflammation. NPT520-34 treatment may thereby address two of the predominate underlying pathophysiological aspects of neurodegenerative disorders such as Parkinson's disease.
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http://dx.doi.org/10.1093/brain/awab214DOI Listing
June 2021

Single-step preparation and image-based counting of minute volumes of human blood.

Lab Chip 2014 Aug 23;14(16):3029-36. Epub 2014 Jun 23.

Center for Biophotonics Science and Technology, University of California, Davis, 2700 Stockton Blvd. Suite 1400, Sacramento, CA 95817, USA.

Current flow-based blood counting devices require significant medical infrastructure and are not appropriate for field use. In this article we report on the development of a sample preparation, measurement, and analysis method that permits automated and accurate counting of red blood cells (RBCs), white blood cells (WBCs), and platelets, as well as allowing a 3-part differential of the WBCs to be performed on extremely small volumes of whole blood. This method is compatible with portable instrumentation that can be deployed in the field. The method consists of serially diluting blood samples first with sodium dodecyl sulfate dissolved in phosphate buffered saline, then in acridine orange dissolved in phosphate buffered saline, followed by fluorescence and dark field imaging with low magnification objectives. Image analysis is performed to extract cell counts and differentials. We performed a paired analysis of 20 volunteers with complete blood count values both within and beyond the normal reference range using a commercial automated hematology analyzer and the image-based method, with the new method achieving accuracies comparable to that of the commercial system. Because the sample preparation and imaging are simple and inexpensive to implement, this method has applications for pediatrics, clinician offices, and global health in regions that do not have access to central hematology laboratories.
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http://dx.doi.org/10.1039/c4lc00567hDOI Listing
August 2014

Neural progenitor implantation restores metabolic deficits in the brain following striatal quinolinic acid lesion.

Exp Neurol 2006 Feb 28;197(2):465-74. Epub 2005 Nov 28.

Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, CA 90095, USA.

Neural progenitor transplantation is a potential treatment for neurodegenerative diseases, including Huntington's disease (HD). In the current study, we tested the potential of rat embryonic neural progenitors expanded in vitro as therapy in the rat quinolinic acid-lesioned striatum, a model that demonstrates some of the pathological features of HD. We used positron emission tomography (PET) to demonstrate that the intrastriatal injection of cultured rat neural progenitors results in improved metabolic function in the striatum and overlying cortex when compared to media-injected controls. Transplanted progenitors were capable of surviving, migrating long distances and differentiating into neurons and glia. The cortices of transplanted animals contained greater numbers of neurons in regions that had shown metabolic improvement. However, histological analysis revealed that only a small fraction of these increased neurons could be accounted for by engrafted cells, indicating that the metabolic sparing was likely the result of a trophic action of the transplanted cells on the host. Behavioral testing of the implanted animals did not reveal improvement in apomorphine-induced rotation. These data demonstrate that progenitor cell implantation results in enhanced metabolic function and sparing of neuron number, but that these functions do not necessarily result in the restoration of complex circuitry.
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http://dx.doi.org/10.1016/j.expneurol.2005.10.023DOI Listing
February 2006

Metabolic correlates of lesion-specific plasticity: an in vivo imaging study.

Brain Res 2004 Mar;1002(1-2):28-34

Department of Neurology, UCLA School of Medicine, Los Angeles, CA 90095, USA.

High-resolution positron emission tomography (microPET) allows for repeated observations of brain function in the same animal. In a previous study, using [(18)F] fluorodeoxyglucose (FDG) microPET, we demonstrated diminished glucose metabolism and subsequent recovery in the Neostriatum and thalamus ipsilateral to cortical aspiration (ASP) lesions. Thermocoagulation (TCL) of pial vessels has been shown to result in the same degree of cortical injury but induce more compensatory re-organization than ASP. In the present work, FDG microPET was used to compare glucose metabolism following both TCL and ASP lesions in order to determine whether metabolic differences correlate with the previously described anatomical and functional changes in the two lesion models. Animals were scanned 3-day, 10-day and 1-month post-injury. Estimated cortical lesion size did not differ between the two models at 1 month following injury. Both lesions induced ipsilateral neostriatal and thalamic hypometabolism 3-day post-injury, with subsequent metabolic improvement over time. However, complete recovery was not observed by 1 month in either group. ASP lesions resulted in an overall greater metabolic deficit in the subcortical structures and a greater cortical deficit 1 month following injury when compared to the TCL. Contralateral cortical glucose metabolism at 3 days following injury was not different in the two lesions. These data demonstrate that the two lesions differ somewhat in their metabolic response to injury, and that the relative hypometabolism observed following ASP may be a reflection of the diminished capacity of the contralateral cortex to compensate for ASP as compared to TCL.
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http://dx.doi.org/10.1016/j.brainres.2003.12.006DOI Listing
March 2004

Evolution of diaschisis in a focal stroke model.

Stroke 2004 Mar 12;35(3):758-63. Epub 2004 Feb 12.

Department of Neurology, David Geffen School of Medicine at University of California at Los Angeles, 710 Westwood Plaza, Los Angeles, CA 90095, USA.

Background And Purpose: Stroke produces diaschisis in adjacent and connected regions. The sequential changes in diaschisis over time and the relationship of regions of diaschisis to functional cortical areas and regions of poststroke neuroplasticity have not been determined.

Methods: Small cortical strokes were produced in the barrel cortex of rats. Relative glucose metabolism was determined in vivo over time with [18F]fluorodeoxyglucose small-animal positron emission tomography. Cerebral blood flow was measured with [14C]iodoantipyrine. Regions of hypometabolism and hypoperfusion were compared with histological damage in the same animals.

Results: Small cortical strokes produce an initial network of hypometabolism in a broad region of cortex adjacent to the stroke and in the striatum and thalamus on day 1. Cerebral blood flow is diminished only immediately around the cortical infarct on day 1. A substantial area of cortex adjacent to the stroke remains hypometabolic on day 8. This persistent cortical hypometabolism occupies the somatosensory cortex, forelimb motor cortex, and second somatosensory area.

Conclusions: Focal stroke produces ipsilateral diaschisis in connected cortical regions that is clearly distant from subtotal damage and may play a role in poststroke neuroplasticity.
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http://dx.doi.org/10.1161/01.STR.0000117235.11156.55DOI Listing
March 2004
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