Distinct and dementia‐related synaptopathy in the hippocampus after military blast exposures

Almeida, Michael F.; Piehler, Thuvan; Carstens, Kelly E.; Zhao, Mei; Samadi, Mahsa; Norton, Christopher J.; Parisian, Catherine M.; Farizatto, Karen L. G.; Bahr, Ben A.

doi:10.1111/bpa.12936

Cited by 9 publications

(4 citation statements)

References 48 publications

(75 reference statements)

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“…Recently, several studies have shown that SIRT1 plays a significant role in induced neuroprotection following caloric restriction (CR) 27 , 28 . CR has also been linked to reduced tau phosphorylation and maintenance of hippocampal neurons 29 , and related Tau pathology is known to be implicated in different types of TBI 30 , 31 . While CR has been shown to increase ketone bodies in the blood, KD does this at a higher level 32 .…”

Section: Introductionmentioning

confidence: 99%

Ketogenic Diet as a potential treatment for traumatic brain injury in mice

Har-Even

Rubovitch

Ratliff

et al. 2021

Sci Rep

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Traumatic brain injury (TBI) is a brain dysfunction without present treatment. Previous studies have shown that animals fed ketogenic diet (KD) perform better in learning tasks than those fed standard diet (SD) following brain injury. The goal of this study was to examine whether KD is a neuroprotective in TBI mouse model. We utilized a closed head injury model to induce TBI in mice, followed by up to 30 days of KD/SD. Elevated levels of ketone bodies were confirmed in the blood following KD. Cognitive and behavioral performance was assessed post injury and molecular and cellular changes were assessed within the temporal cortex and hippocampus. Y-maze and Novel Object Recognition tasks indicated that mTBI mice maintained on KD displayed better cognitive abilities than mTBI mice maintained on SD. Mice maintained on SD post-injury demonstrated SIRT1 reduction when compared with uninjured and KD groups. In addition, KD management attenuated mTBI-induced astrocyte reactivity in the dentate gyrus and decreased degeneration of neurons in the dentate gyrus and in the cortex. These results support accumulating evidence that KD may be an effective approach to increase the brain’s resistance to damage and suggest a potential new therapeutic strategy for treating TBI.

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Section: Introductionmentioning

confidence: 99%

Ketogenic Diet as a potential treatment for traumatic brain injury in mice

Har-Even

Rubovitch

Ratliff

et al. 2021

Sci Rep

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“…The explants displayed long‐term maintenance of the major neuronal subfields of the hippocampus (Figure 1B) and their dense processes populated with evident staining of synaptic terminals (Figure 1C–E). Former studies reported that the slice cultures exhibit connectivity, plasticity and pathogenic responsiveness as found in vivo 11,13,50–52 . Here, we used an NMDA infusion period that led to pathogenic changes as previously described 6,51 …”

Section: Resultsmentioning

confidence: 99%

“…Former studies reported that the slice cultures exhibit connectivity, plasticity and pathogenic responsiveness as found in vivo. 11 , 13 , 50 , 51 , 52 Here, we used an NMDA infusion period that led to pathogenic changes as previously described. 6 , 51 The protocol for the excitotoxic stimulation and subsequent measuring of gene expression profiles is shown in Figure 1F , in which the explants were infused with NMDA for 20 min followed by rapid washout in the presence of glutamatergic antagonists for precise insult duration due to quenching any further excitatory activation.…”

Section: Resultsmentioning

confidence: 99%

Excitotoxic stimulation activates distinct pathogenic and protective expression signatures in the hippocampus

Caba

Sherman

Farizatto

et al. 2021

J Cellular Molecular Medi

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Excitotoxic events underlying ischaemic and traumatic brain injuries activate degenerative and protective pathways, particularly in the hippocampus. To understand opposing pathways that determine the brain's response to excitotoxicity, we used hippocampal explants, thereby eliminating systemic variables during a precise protocol of excitatory stimulation. N‐methyl‐d‐aspartate (NMDA) was applied for 20 min and total RNA isolated one and 24 h later for neurobiology‐specific microarrays. Distinct groups of genes exhibited early vs. delayed induction, with 63 genes exclusively reduced 24‐h post‐insult. Egr‐1 and NOR‐1 displayed biphasic transcriptional modulation: early induction followed by delayed suppression. Opposing events of NMDA‐induced genes linked to pathogenesis and cell survival constituted the early expression signature. Delayed degenerative indicators (up‐regulated pathogenic genes, down‐regulated pro‐survival genes) and opposing compensatory responses (down‐regulated pathogenic genes, up‐regulated pro‐survival genes) generated networks with temporal gene profiles mirroring coexpression network clustering. We then used the expression profiles to test whether NF‐κB, a potent transcription factor implicated in both degenerative and protective pathways, is involved in the opposing responses. The NF‐κB inhibitor MG‐132 indeed altered NMDA‐mediated transcriptional changes, revealing components of opposing expression signatures that converge on the single response element. Overall, this study identified counteracting avenues among the distinct responses to excitotoxicity, thereby suggesting multi‐target treatment strategies and implications for predictive medicine.

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“…Upon the completion of studies using POD device in rats, we will work with Impel Neuropharma (human POD device) to optimize IN delivery to humans. In addition to benefitting cortical impact injuries, NSCs could also impart benefits in others CNS injury models such as ischemic or hemorrhage stroke [32][33][34][35] and blast-induced injuries 81,82 . Thus, development of cellular therapy of therapeutic NSCs delivered IN represents a promising method for treating patients with a wide range of TBI and other CNS pathologies [83][84][85] .…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective potential of intranasally delivered L-myc immortalized human neural stem cells in female rats after a controlled cortical impact injury

Amirbekyan,

Cheng,

Adhikarla

et al. 2023

Preprint

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Efficacious stem cell-based therapies for traumatic brain injury (TBI) depend on successful delivery, migration, and engraftment of stem cells to induce neuroprotection. L-myc expressing human neural stem cells (LMNSC008) demonstrate an inherent tropism to injury sites after intranasal (IN) administration. We hypothesize that IN delivered LMNSC008 cells migrate to primary and secondary injury sites and modulate biomarkers associated with neuroprotection and tissue regeneration. To test this, immunocompetent adult female rats received a controlled cortical impact injury (CCI) or sham surgery. LMNSC008 cells or a vehicle (VEH) were administered IN on postoperative days 7, 9, 11, 13, 15, and 17. The distribution and migration of eGFP-expressing LMNSC008 cells were quantified over 1 mm-thick optically cleared (CLARITY) coronal brain sections from TBI and SHAM controls. NSC migration was observed along white matter tracts projecting toward the hippocampus and regions of TBI. ELISA and Nanostring assays revealed a shift in tissue gene expression in LMNSC008 treated rats relative to controls. LMNSC008 treatment reduced expression of genes and pathways involved in inflammatory response, microglial function, and various cytokines and receptors. The data demonstrate a robust proof-of-concept for LMNSC008 therapy for TBI and provides a strong rationale for IN delivery for translation in TBI patients.

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Distinct and dementia‐related synaptopathy in the hippocampus after military blast exposures

Cited by 9 publications

References 48 publications

Ketogenic Diet as a potential treatment for traumatic brain injury in mice

Ketogenic Diet as a potential treatment for traumatic brain injury in mice

Excitotoxic stimulation activates distinct pathogenic and protective expression signatures in the hippocampus

Neuroprotective potential of intranasally delivered L-myc immortalized human neural stem cells in female rats after a controlled cortical impact injury

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