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Title: D-cycloserine improves cognitive deficits in a mouse model of global neuroinflammation with a wide treatment window - a novel treatment approach

Authors:
; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL)
Sponsoring Org.:
USDOE SC OFFICE OF BIOLOGICAL & ENVIRONMENTAL RESEARCH
OSTI Identifier:
1160055
Report Number(s):
BNL-106200-2014-JA
R&D Project: MO-085; KP1602010
DOE Contract Number:
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Molecular Neuroscience; Journal Volume: 53; Journal Issue: 1; Conference: 22nd Annual Meeting of the Israel-Society-for-Neuroscience (ISFN) / 2nd Bi National Italy-Israel Neuroscience Meeting; Eilat, Israel; 20131214 through 20131217
Country of Publication:
United States
Language:
English
Subject:
61 RADIATION PROTECTION AND DOSIMETRY

Citation Formats

Liraz-Zaltsman S., Biegon A., Alexandrovich, A. G., Yaka, R., and Shohami, E. D-cycloserine improves cognitive deficits in a mouse model of global neuroinflammation with a wide treatment window - a novel treatment approach. United States: N. p., 2014. Web.
Liraz-Zaltsman S., Biegon A., Alexandrovich, A. G., Yaka, R., & Shohami, E. D-cycloserine improves cognitive deficits in a mouse model of global neuroinflammation with a wide treatment window - a novel treatment approach. United States.
Liraz-Zaltsman S., Biegon A., Alexandrovich, A. G., Yaka, R., and Shohami, E. Fri . "D-cycloserine improves cognitive deficits in a mouse model of global neuroinflammation with a wide treatment window - a novel treatment approach". United States. doi:.
@article{osti_1160055,
title = {D-cycloserine improves cognitive deficits in a mouse model of global neuroinflammation with a wide treatment window - a novel treatment approach},
author = {Liraz-Zaltsman S. and Biegon A. and Alexandrovich, A. G. and Yaka, R. and Shohami, E.},
abstractNote = {},
doi = {},
journal = {Journal of Molecular Neuroscience},
number = 1,
volume = 53,
place = {United States},
year = {Fri Aug 01 00:00:00 EDT 2014},
month = {Fri Aug 01 00:00:00 EDT 2014}
}
  • Our previous findings suggest that mitochondrial dysfunction is the mechanism underlying cognitive deficits induced by domoic acid (DA). Ursolic acid (UA), a natural triterpenoid compound, possesses many important biological functions. Evidence shows that UA can activate PI3K/Akt signaling and suppress Forkhead box protein O1 (FoxO1) activity. FoxO1 is an important regulator of mitochondrial function. Here we investigate whether FoxO1 is involved in the oxidative stress-induced mitochondrial dysfunction in DA-treated mice and whether UA inhibits DA-induced mitochondrial dysfunction and cognitive deficits through regulating the PI3K/Akt and FoxO1 signaling pathways. Our results showed that FoxO1 knockdown reversed the mitochondrial abnormalities and cognitivemore » deficits induced by DA in mice through decreasing HO-1 expression. Mechanistically, FoxO1 activation was associated with oxidative stress-induced JNK activation and decrease of Akt phosphorylation. Moreover, UA attenuated the mitochondrial dysfunction and cognitive deficits through promoting Akt phosphorylation and FoxO1 nuclear exclusion in the hippocampus of DA-treated mice. LY294002, an inhibitor of PI3K/Akt signaling, significantly decreased Akt phosphorylation in the hippocampus of DA/UA mice, which weakened UA actions. These results suggest that UA could be recommended as a possible candidate for the prevention and therapy of cognitive deficits in excitotoxic brain disorders. - Highlights: • Ursolic acid (UA) is a naturally triterpenoid compound. • UA attenuated the mitochondrial dysfunction and cognitive deficits. • Mechanistically, UA activates PI3K/Akt signaling and suppresses FoxO1 activity. • UA could be recommended as a possible candidate for anti-excitotoxic brain disorders.« less
  • It has been long thought that hyperactivation of N-methyl-D-aspartate (NMDA) receptors underlies neurological decline after traumatic brain injury. However, all clinical trials with NMDA receptor antagonists failed. Since NMDA receptors are down-regulated from 4 h to 2 weeks after brain injury, activation at 24 h, rather than inhibition, of these receptors, was previously shown to be beneficial in mice. Here, we tested the therapeutic window, dose regimen and mechanism of action of the NMDA receptor partial agonist d-cycloserine (DCS) in traumatic brain injury. Male mice were subjected to trauma using a weight-drop model, and administered 10 mg/kg (i.p.) DCS ormore » vehicle once (8, 16, 24, or 72 h) twice (24 and 48 h) or three times (24, 48 and 72 h). Functional recovery was assessed for up to 60 days, using a Neurological Severity Score that measures neurobehavioral parameters. In all groups in which treatment was begun at 24 or 72 h neurobehavioral function was significantly better than in the vehicle-treated groups. Additional doses, on days 2 and 3 did not further improve recovery. Mice treated at 8 h or 16 h post injury did not differ from the vehicle-treated controls. Co-administration of the NMDA receptor antagonist MK-801 completely blocked the protective effect of DCS given at 24 h. Infarct volume measured by 2,3,5-triphenyltetrazolium chloride staining at 48 h or by cresyl violet at 28 days was not affected by DCS treatment. Since DCS is used clinically for other indications, the present study offers a novel approach for treating human traumatic brain injury with a therapeutic window of at least 24 h.« less
  • Deep brain stimulation (DBS) is an established treatment for advanced Parkinson's disease (PD). The procedure entails intracranial implantation of an electrode in a specific brain structure followed by chronic stimulation. Although the beneficial effects of DBS on motor symptoms in PD are well known, it is often accompanied by cognitive impairments, the origin of which is not fully understood. To explore the possible contribution of the surgical procedure itself, we studied the effect of electrode implantation in the subthalamic nucleus (STN) on regional neuroinflammation and memory function in rats implanted bilaterally with stainless steel electrodes. Age-matched sham and intact ratsmore » were used as controls. Brains were removed 1 or 8 weeks post-implantation and processed for in vitro autoradiography with [(3)H]PK11195, an established marker of microglial activation. Memory function was assessed by the novel object recognition test (ORT) before surgery and 2 and 8 weeks after surgery. Electrode implantation produced region-dependent changes in ligand binding density in the implanted brains at 1 as well as 8 weeks post-implantation. Cortical regions showed more intense and widespread neuroinflammation than striatal or thalamic structures. Furthermore, implanted animals showed deficits in ORT performance 2 and 8 weeks post-implantation. Thus, electrode implantation resulted in a widespread and persistent neuroinflammation and sustained memory impairment. These results suggest that the insertion and continued presence of electrodes in the brain, even without stimulation, may lead to inflammation-mediated cognitive deficits in susceptible individuals, as observed in patients treated with DBS.« less
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