Genetic and pharmacological intervention of the p75NTR pathway alters morphological and behavioural recovery following traumatic brain injury in mice

Alder, Janet; Fujioka, Wendy; Giarratana, Anna O.; Wissocki, Jenna; Thakkar, Keya; Vuong, Phung; Patel, Bijal; Chakraborty, Tandra R.; Elsabeh, Rami; Parikh, Ankit; Girn, Hartaj; Crockett, David P.; Thakker‐Varia, Smita

doi:10.3109/02699052.2015.1088963

Cited by 33 publications

(61 citation statements)

References 110 publications

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“…6A). We and others have observed this behavior in previous stud- ies (Cernak et al, 2014;Chen et al, 2014;Rowe et al, 2014;Alder et al, 2016), and since it was independent of the injury, we did not investigate this matter further.…”

Section: Tg-c73a Mice Perform Better Than Non-tg and Tg-wt Mice On Thmentioning

confidence: 76%

“…The findings reported here that show that oxidation of K ϩ channels contribute to cognitive impairment underscore the high degree of conservation of this mechanism of neuronal vulnerability and further broaden its potential relevance. For example, it is well established that the aging hippocampus of rodents develops hyperexcitability (Landfield et al, 1986;Barnes et al, 1987;Barnes, 1994;Papatheodoropoulos and Kostopoulos, 1996), and it may not be coincidental that KCNB1 undergoes oxidation in the brains of naturally aging mice (Cotella et al, 2012). Moreover, KCNB1 channels are oxidized in hippocampal neurons of the 3x-Tg-AD mouse where they promote hyperexcitability (Frazzini et al, 2016), while inhibition of Src kinases attenuates microgliosis in BV2 murine cells incubated with ␤-amyloid oligomers (Dhawan and Combs, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…8B; cortex, Table 1), a marker for neurodegeneration (Schmued et al, 1997); and activated caspase-3 (hippocampus, Fig. 8C; cortex, Table 1), a marker for neuronal apoptosis (caspase-3 staining colocalizes with NeuN but not GFAP; Beer et al, 2000;Clark et al, 2000;McEwen and Springer, 2005;Alder et al, 2016). Representative images of GFAP staining in cortical sections of the various genotypes at 7 and 21 dpi along with quantitative analyses are shown in Figure 7.…”

Section: Tg-c73a Mice Perform Better Than Non-tg and Tg-wt Mice In Thmentioning

confidence: 99%

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Oxidation of KCNB1 Potassium Channels Causes Neurotoxicity and Cognitive Impairment in a Mouse Model of Traumatic Brain Injury

Parakramaweera

Teng

et al. 2016

J. Neurosci.

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The delayed rectifier potassium (K ϩ ) channel KCNB1 (Kv2.1), which conducts a major somatodendritic current in cortex and hippocampus, is known to undergo oxidation in the brain, but whether this can cause neurodegeneration and cognitive impairment is not known. Here, we used transgenic mice harboring human KCNB1 wild-type (Tg-WT) or a nonoxidable C73A mutant (Tg-C73A) in cortex and hippocampus to determine whether oxidized KCNB1 channels affect brain function. Animals were subjected to moderate traumatic brain injury (TBI), a condition characterized by extensive oxidative stress. Dasatinib, a Food and Drug Administration-approved inhibitor of Src tyrosine kinases, was used to impinge on the proapoptotic signaling pathway activated by oxidized KCNB1 channels. Thus, typical lesions of brain injury, namely, inflammation (astrocytosis), neurodegeneration, and cell death, were markedly reduced in Tg-C73A and dasatinib-treated non-Tg animals. Accordingly, Tg-C73A mice and non-Tg mice treated with dasatinib exhibited improved behavioral outcomes in motor (rotarod) and cognitive (Morris water maze) assays compared to controls. Moreover, the activity of Src kinases, along with oxidative stress, were significantly diminished in Tg-C73A brains. Together, these data demonstrate that oxidation of KCNB1 channels is a contributing mechanism to cellular and behavioral deficits in vertebrates and suggest a new therapeutic approach to TBI.

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Section: Tg-c73a Mice Perform Better Than Non-tg and Tg-wt Mice On Thmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Section: Tg-c73a Mice Perform Better Than Non-tg and Tg-wt Mice In Thmentioning

confidence: 99%

See 1 more Smart Citation

Oxidation of KCNB1 Potassium Channels Causes Neurotoxicity and Cognitive Impairment in a Mouse Model of Traumatic Brain Injury

Parakramaweera

Teng

et al. 2016

J. Neurosci.

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“…In the previous investigation, the assessment of synaptic proteins utilized the penumbra as opposed to the cortex directly below the injury location. There are several instances where a natural compound has been shown to significantly reduce secondary injury cascades but fail to improve cognitive performance in the MWM [1, 11, 21]. Somewhat surprising is the fact that caffeic acid, which is one of the main components of PYC, has been shown to significantly reduce lesion volume and improve cognition when administered post-trauma [56].…”

Section: Discussionmentioning

confidence: 99%

Cognitive assessment of pycnogenol therapy following traumatic brain injury

Roberts

2016

Neuroscience Letters

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We have previously shown that pycnogenol (PYC) increases antioxidants, decreases oxidative stress, suppresses neuroinflammation and enhances synaptic plasticity following traumatic brain injury (TBI). Here, we investigate the effects of PYC on cognitive function following a controlled cortical impact (CCI). Adult Sprague-Dawley rats received a CCI injury followed by an intraperitoneal injection of PYC (50 or 100 mg/kg). Seven days post trauma, subjects were evaluated in a Morris water maze (MWM) and evaluated for changes in lesion volume. Some animals were evaluated at 48h for hippocampal Fluoro-jade B (FJB) staining. The highest dose of PYC therapy significantly reduced lesion volume, with no improvement in MWM compared to vehicle controls. PYC failed to reduce the total number of FJB positive neurons in the hippocampus. These results suggest that the reduction of oxidative stress and neuroinflammation are not the key components of the secondary injury that contribute to cognitive deficits following TBI.

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“…Studies with animal TBI models suggested that some of the pathological and behavioral effects of TBI might be due to damage signaling activated by pro-neurotrophin/p75 association, which prevails over the protective signaling activated by mature neurotrophin/Trk binding [118]. Trk-signals are normally required for neuronal maintenance and function, and defects in Trk activation are associated with early stages of neurodegeneration [119,120,121].…”

Section: What Are the Roles Of Neurotrophins After Acute Neural Inmentioning

confidence: 99%

Neurotrauma: The Crosstalk between Neurotrophins and Inflammation in the Acutely Injured Brain

Meirelles

Simon

Regner

2017

IJMS

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Traumatic brain injury (TBI) is a major cause of morbidity and mortality among young individuals worldwide. Understanding the pathophysiology of neurotrauma is crucial for the development of more effective therapeutic strategies. After the trauma occurs, immediate neurologic damage is produced by the traumatic forces; this primary injury triggers a secondary wave of biochemical cascades together with metabolic and cellular changes, called secondary neural injury. In the scenario of the acutely injured brain, the ongoing secondary injury results in ischemia and edema culminating in an uncontrollable increase in intracranial pressure. These areas of secondary injury progression, or areas of “traumatic penumbra”, represent crucial targets for therapeutic interventions. Neurotrophins are a class of signaling molecules that promote survival and/or maintenance of neurons. They also stimulate axonal growth, synaptic plasticity, and neurotransmitter synthesis and release. Therefore, this review focuses on the role of neurotrophins in the acute post-injury response. Here, we discuss possible endogenous neuroprotective mechanisms of neurotrophins in the prevailing environment surrounding the injured areas, and highlight the crosstalk between neurotrophins and inflammation with focus on neurovascular unit cells, particularly pericytes. The perspective is that neurotrophins may represent promising targets for research on neuroprotective and neurorestorative processes in the short-term following TBI.

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Genetic and pharmacological intervention of the p75NTR pathway alters morphological and behavioural recovery following traumatic brain injury in mice

Abstract: Many of the pathological and behavioural consequences of TBI might be due to activation of the pro-neurotrophin/p75 toxic pathway overriding the protective mechanisms of the mature neurotrophin/Trk pathway. Targeting p75 can be a novel strategy to counteract the damaging effects of TBI.

Cited by 33 publications

References 110 publications

Oxidation of KCNB1 Potassium Channels Causes Neurotoxicity and Cognitive Impairment in a Mouse Model of Traumatic Brain Injury

Oxidation of KCNB1 Potassium Channels Causes Neurotoxicity and Cognitive Impairment in a Mouse Model of Traumatic Brain Injury

Cognitive assessment of pycnogenol therapy following traumatic brain injury

Neurotrauma: The Crosstalk between Neurotrophins and Inflammation in the Acutely Injured Brain

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