The Novel Compound LOE 908 Attenuates Acute Neuromotor Dysfunction but Not Cognitive Impairment or Cortical Tissue Loss Following Traumatic Brain Injury in Rats

Cheney, Jessica A.; Brown, Adrienne L.; Bareyre, Florence M.; Russ, Andrew B.; Weisser, Justin D.; Ensinger, Helmut A.; Leusch, Andreas; Raghupathi, Ramesh; Saatman, Kathryn E.

doi:10.1089/neu.2000.17.83

Cited by 18 publications

(18 citation statements)

References 43 publications

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“…Further, the decrease in calpain-mediated spectrin proteolysis would suggest that the effects of MS-153 are mediated via a reduction of calcium influx into injured cells. 46 Several classes of compounds including NMDA receptor antagonists 81 and compounds that target calcium influx, 79,82 have been shown to ameliorate cellular damage and neurologic deficits, as well as cognitive decline and motor impairments caused by TBI. In models of brain injury, glutamate receptor antagonists, such as kynurenate, 83 NBQX, and CGS 19755, 84 have been reported to partially ameliorate cytoskeletal injury with preserved immuno-labeling of MAP-2 and to reduce the accumulation of calpain-cleaved spectrin byproducts.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective Effects of the Glutamate Transporter Activator (R)-(−)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153) following Traumatic Brain Injury in the Adult Rat

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Fox

Zoubroulis

et al. 2016

Journal of Neurotrauma

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Traumatic brain injury (TBI) in humans and in animals leads to an acute and sustained increase in tissue glutamate concentrations within the brain, triggering glutamate-mediated excitotoxicity. Excitatory amino acid transporters (EAATs) are responsible for maintaining extracellular central nervous system glutamate concentrations below neurotoxic levels. Our results demonstrate that as early as 5 min and up to 2 h following brain trauma in brain-injured rats, the activity (V max ) of EAAT2 in the cortex and the hippocampus was significantly decreased, compared with sham-injured animals. The affinity for glutamate (K M ) and the expression of glutamate transporter 1 (GLT-1) and glutamate aspartate transporter (GLAST) were not altered by the injury. Administration of (R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153), a GLT-1 activator, beginning immediately after injury and continuing for 24 h, significantly decreased neurodegeneration, loss of microtubule-associated protein 2 and NeuN (+) immunoreactivities, and attenuated calpain activation in both the cortex and the hippocampus at 24 h after the injury; the reduction in neurodegeneration remained evident up to 14 days post-injury. In synaptosomal uptake assays, MS-153 up-regulated GLT-1 activity in the naïve rat brain but did not reverse the reduced activity of GLT-1 in traumatically-injured brains. This study demonstrates that administration of MS-153 in the acute post-traumatic period provides acute and long-term neuroprotection for TBI and suggests that the neuroprotective effects of MS-153 are related to mechanisms other than GLT-1 activation, such as the inhibition of voltage-gated calcium channels.

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Section: Discussionmentioning

confidence: 99%

Neuroprotective Effects of the Glutamate Transporter Activator (R)-(−)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153) following Traumatic Brain Injury in the Adult Rat

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Fox

Zoubroulis

et al. 2016

Journal of Neurotrauma

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“…The Morris water maze (MWM) Visuo-Spatial Learning Paradigm (36, 37) quantified post-traumatic anterograde amnesia and spatial learning. The MWM consisted of a 10 cm diameter platform submerged 1 cm below the surface of a 25 cm deep pool of water.…”

Section: Methodsmentioning

confidence: 99%

Primary Blast Traumatic Brain Injury in the Rat: Relating Diffusion Tensor Imaging and Behavior

Budde¹,

Shah²,

McCrea³

et al. 2013

Front. Neurol.

137

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The incidence of traumatic brain injury (TBI) among military personnel is at its highest point in U.S. history. Experimental animal models of blast have provided a wealth of insight into blast injury. The mechanisms of neurotrauma caused by blast, however, are still under debate. Specifically, it is unclear whether the blast shockwave in the absence of head motion is sufficient to induce brain trauma. In this study, the consequences of blast injury were investigated in a rat model of primary blast TBI. Animals were exposed to blast shockwaves with peak reflected overpressures of either 100 or 450 kPa (39 and 110 kPa incident pressure, respectively) and subsequently underwent a battery of behavioral tests. Diffusion tensor imaging (DTI), a promising method to detect blast injury in humans, was performed on fixed brains to detect and visualize the spatial dependence of blast injury. Blast TBI caused significant deficits in memory function as evidenced by the Morris Water Maze, but limited emotional deficits as evidenced by the Open Field Test and Elevated Plus Maze. Fractional anisotropy, a metric derived from DTI, revealed significant brain abnormalities in blast-exposed animals. A significant relationship between memory deficits and brain microstructure was evident in the hippocampus, consistent with its role in memory function. The results provide fundamental insight into the neurological consequences of blast TBI, including the evolution of injury during the sub-acute phase and the spatially dependent pattern of injury. The relationship between memory dysfunction and microstructural brain abnormalities may provide insight into the persistent cognitive difficulties experienced by soldiers exposed to blast neurotrauma and may be important to guide therapeutic and rehabilitative efforts.

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“…15,90 The paradigm consisted of three days of testing on post-injury days 1, 2, and 3. Each day of testing included one set of four trials for a total of 12 trials across three days.…”

Section: Experimental Groupsmentioning

confidence: 99%

Head Rotational Acceleration Characteristics Influence Behavioral and Diffusion Tensor Imaging Outcomes Following Concussion

et al. 2014

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A majority of traumatic brain injuries (TBI) in motor vehicle crashes and sporting environments are mild and caused by high-rate acceleration of the head. For injuries caused by rotational acceleration, both magnitude and duration of the acceleration pulse were shown to influence injury outcomes. This study incorporated a unique rodent model of rotational acceleration-induced mild TBI (mTBI) to quantify independent effects of magnitude and duration on behavioral and neuroimaging outcomes. Ninety-two Sprague– Dawley rats were exposed to head rotational acceleration at peak magnitudes of 214 or 350 krad/s2 and acceleration pulse durations of 1.6 or 3.4 ms in a full factorial design. Rats underwent a series of behavioral tests including the Composite Neuroscore (CN), Elevated Plus Maze (EPM), and Morris Water Maze (MWM). Ex vivo diffusion tensor imaging (DTI) of the fixed brains was conducted to assess the effects of rotational injury on brain microstructure as revealed by the parameter fractional anisotropy (FA). While the injury did not cause significant locomotor or cognitive deficits measured with the CN and MWM, respectively, a main effect of duration was consistently observed for the EPM. Increased duration caused significantly greater activity and exploratory behaviors measured as open arm time and number of arm changes. DTI demonstrated significant effects of both magnitude and duration, with the FA of the amygdala related to both the magnitude and duration. Increased duration also caused FA changes at the interface of gray and white matter. Collectively, the findings demonstrate that the consequences of rotational acceleration mTBI were more closely associated with duration of the rotational acceleration impulse, which is often neglected as an independent factor, and highlight the need for animal models of TBI with strong biomechanical foundations to associate behavioral outcomes with brain microstructure.

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The Novel Compound LOE 908 Attenuates Acute Neuromotor Dysfunction but Not Cognitive Impairment or Cortical Tissue Loss Following Traumatic Brain Injury in Rats

Cited by 18 publications

References 43 publications

Neuroprotective Effects of the Glutamate Transporter Activator (R)-(−)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153) following Traumatic Brain Injury in the Adult Rat

Neuroprotective Effects of the Glutamate Transporter Activator (R)-(−)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153) following Traumatic Brain Injury in the Adult Rat

Primary Blast Traumatic Brain Injury in the Rat: Relating Diffusion Tensor Imaging and Behavior

Head Rotational Acceleration Characteristics Influence Behavioral and Diffusion Tensor Imaging Outcomes Following Concussion

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