The Polyamine Inhibitor Alpha-Difluoromethylornithine Modulates Hippocampus-Dependent Function after Single and Combined Injuries

Rosi, Susanna; Ferguson, Ryan; Fishman, Kelly; Allen, Antiño R.; Raber, Jacob; Fike, John R.

doi:10.1371/journal.pone.0031094

Cited by 17 publications

(23 citation statements)

References 63 publications

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“…The hippocampus has been shown to be critically involved in learning and memory, and the results of this current study show that these functions are affected by RCI and are in agreement with our previous studies (9). Hippocampal-dependent learning and memory are strongly influenced by the activity of neural stem cells and their proliferative progeny (31).…”

Section: Discussionsupporting

confidence: 94%

“…However, the RCI mice were impaired while the mice receiving radiation only did not display cognitive deficiency. Given these findings, the data suggest that the generation of newly born neurons per se may not be a critical factor in the cognitive performance changes observed here, which supports previous reports on RCI (9, 34). …”

Section: Discussionsupporting

confidence: 91%

“…Whole-body irradiation was performed using a 137 Cs irradiator (Gamma cell 3000; MDS Nordion Inc., Ottawa, ON, Canada) as previously described (9). Animals were irradiated individually in a specially designed restrainer that fit into the irradiator and allowed minimal movement.…”

Section: Methodsmentioning

confidence: 99%

“…Images were reconstructed as described previously (9). Briefly, mosaics were collected with a Zeiss Axio Imager ApoTome microscope using a 20× objective (Carl Zeiss, Hertfordshire, UK).…”

Section: Methodsmentioning

confidence: 99%

“…Our earlier work showed that DFMO treatment reduced radiation-induced necrosis, vascular permeability and associated vasogenic edema after focal radiation-induced injury (6–8). We recently demonstrated that when administered immediately after injury and for 41 consecutive days, DFMO effectively reversed cognitive impairments after trauma alone and particularly after RCI (9). To determine if DFMO could ameliorate the adverse effects of RCI when drug delivery was delayed, we started the DFMO treatment 24 h after a single or combined injury and continued the DFMO treatment for 41 consecutive days.…”

Section: Introductionmentioning

confidence: 99%

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Delayed Administration of Alpha-Difluoromethylornithine Prevents Hippocampus-Dependent Cognitive Impairment after Single and Combined Injury in Mice

et al. 2014

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Radiation exposure due to radiological terrorism and military circumstances are a continuing threat for the civilian population. In an uncontrolled radiation event, it is likely that there will be other types of injury involved, including trauma. While radiation combined injury is recognized as an area of great significance, overall there is a paucity of information regarding the mechanisms underlying the interactions between irradiation and other forms of injury, or what countermeasures might be effective in ameliorating such changes. The objective of this study was to determine if difluoromethylornithine (DFMO) could reduce the adverse effects of single or combined injury if administered beginning 24 h after exposure. Eight-week-old C57BL/J6 young-adult male mice received whole-body cesium-137 (137Cs) irradiation with 4 Gy. Immediately after irradiation, unilateral traumatic brain injury was induced using a controlled cortical impact system. Forty-four days postirradiation, animals were tested for hippocampus-dependent cognitive performance in the Morris water maze. After cognitive testing, animals were euthanized and their brains snap frozen for immunohisto-chemical assessment of neuroinflammation (activated microglia) and neurogenesis in the hippocampal dentate gyrus. Our data show that single and combined injuries induced variable degrees of hippocampus-dependent cognitive dysfunction, and when given 24 h post trauma, DFMO treatment ameliorated those effects. Cellular changes including neuro-genesis and numbers of activated microglia were generally not associated with the cognitive changes. Further analyses also revealed that DFMO increased hippocampal protein levels of the antioxidants thioredoxin 1 and peroxiredoxin 3 compared to vehicle treated animals. While the mechanisms responsible for the improvement in cognition after DFMO treatment are not yet clear, these results constitute a basis for further development of DFMO as a countermeasure for ameliorating the of risks for cognitive dysfunction in individuals subjected to trauma and radiation combined injury.

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Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

“…Images were reconstructed as described previously (9). Briefly, mosaics were collected with a Zeiss Axio Imager ApoTome microscope using a 20× objective (Carl Zeiss, Hertfordshire, UK).…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Delayed Administration of Alpha-Difluoromethylornithine Prevents Hippocampus-Dependent Cognitive Impairment after Single and Combined Injury in Mice

et al. 2014

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Aβ stimulates microglial activation through antizyme‐dependent downregulation of ornithine decarboxylase

Cheng

Chang²,

Chang³

et al. 2018

Journal Cellular Physiology

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Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders. Its pathology is associated with the deposition of amyloid β (Aβ), an abnormal extracellular peptide. Moreover, its pathological progression is closely accompanied by neuroinflammation. Specifically, Aβ‐associated microglial overactivation may have the central role in AD pathogenesis. Interestingly, arginine metabolism may contribute to the equilibrium between M1 and M2 microglia. However, little is known about the involvement of arginine metabolism in Aβ‐induced microglial neuroinflammation and neurotoxicity. Moreover, the underlying mechanism by which Aβ induces the transition of microglia to the M1 phenotype remains unclear. In this study, we investigated the role of Aβ in mediating microglial activation and polarization both in vitro and in vivo. Our results demonstrated that under the Aβ treatment, ornithine decarboxylase (ODC), a rate‐limiting enzyme in the regulation of arginine catabolism, regulates microglial activation by altering the antizyme (AZ) + 1 ribosomal frameshift. Furthermore, the restoration of ODC protein expression levels has profound effects on inhibition of Aβ‐induced M1 markers and thus attenuates microglial‐mediated cytotoxicity. Altogether, our findings suggested that Aβ may contribute to M1‐like activation by disrupting the balance between ODC and AZ in microglia.

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Oxidative stress and redox regulation on hippocampal-dependent cognitive functions

Huang

Leu

Zou

2015

Archives of Biochemistry and Biophysics

121

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Hippocampal-dependent cognitive functions rely on production of new neurons and maintenance of dendritic structures to provide the synaptic plasticity needed for learning and formation of new memories. Hippocampal formation is exquisitely sensitive to patho-physiological changes, and reduced antioxidant capacity and exposure to low dose irradiation can significantly impede hippocampal-dependent functions of learning and memory by reducing the production of new neurons and alter dendritic structures in the hippocampus. Although the mechanism leading to impaired cognitive functions is complex, persistent oxidative stress likely plays an important role in the SOD-deficient and radiation-exposed hippocampal environment. Aging is associated with increased production of pro-oxidants and accumulation of oxidative end products. Similar to the hippocampal defects observed in SOD-deficient mice and mice exposed to low dose irradiation, reduced capacity in learning and memory, diminishing hippocampal neurogenesis, and altered dendritic network are universal in the aging brains. Given the similarities in cellular and structural changes in the aged, SOD-deficient, and radiation-exposed hippocampal environment and the corresponding changes in cognitive decline, understanding the shared underlying mechanism will provide more flexible and efficient use of SOD deficiency or irradiation to model age-related changes in cognitive functions and identify potential therapeutic or intervention methods.

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The Polyamine Inhibitor Alpha-Difluoromethylornithine Modulates Hippocampus-Dependent Function after Single and Combined Injuries

Cited by 17 publications

References 63 publications

Delayed Administration of Alpha-Difluoromethylornithine Prevents Hippocampus-Dependent Cognitive Impairment after Single and Combined Injury in Mice

Delayed Administration of Alpha-Difluoromethylornithine Prevents Hippocampus-Dependent Cognitive Impairment after Single and Combined Injury in Mice

Aβ stimulates microglial activation through antizyme‐dependent downregulation of ornithine decarboxylase

Oxidative stress and redox regulation on hippocampal-dependent cognitive functions

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