Selective CDK Inhibitor Limits Neuroinflammation and Progressive Neurodegeneration after Brain Trauma

Kabadi, Shruti V.; Stoica, Bogdan A.; Byrnes, Kimberly R.; Hanscom, Marie; Loane, David J.; Faden, Alan I.

doi:10.1038/jcbfm.2011.117

Cited by 83 publications

(115 citation statements)

References 46 publications

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“…33 Our analysis was focused on the dorsal region of the hippocampus, in the area directly underneath the impact site. The sampled region for each subfield was demarcated in the injured hemisphere and cresyl violet neuronal cell bodies were counted.…”

Section: Assessment Of Neuronal Cell Loss In the Hippocampal Sub-regionsmentioning

confidence: 99%

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Comparing the Predictive Value of Multiple Cognitive, Affective, and Motor Tasks after Rodent Traumatic Brain Injury

Zhao

Loane

Murray

et al. 2012

Journal of Neurotrauma

102

140

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Controlled cortical impact injury (CCI) is a widely-used, clinically-relevant model of traumatic brain injury (TBI). Although functional outcomes have been used for years in this model, little work has been done to compare the predictive value of various cognitive and sensorimotor assessment tests, singly or in combination. Such information would be particularly useful for assessing mechanisms of injury or therapeutic interventions. Following isoflurane anesthesia, C57BL/6 mice were subjected to sham, mild (5.0 m/sec), moderate (6.0 m/sec), or severe (7.5 m/sec) CCI. A battery of behavioral tests were evaluated and compared, including the standard Morris water maze (sMWM), reversal Morris water maze (rMWM), novel object recognition (NOR), passive avoidance (PA), tail-suspension (TS), beam walk (BW), and open-field locomotor activity. The BW task, performed at post-injury days (PID) 0, 1, 3, 7, 14, 21, and 28, showed good discrimination as a function of injury severity. The sMWM and rMWM tests (PID 14-23), as well as NOR (PID 24 and 25), effectively discriminated spatial and novel object learning and memory across injury severity levels. Notably, the rMWM showed the greatest separation between mild and moderate/severe injury. PA (PID 27 and 28) and TS (PID 24) also reflected differences across injury levels, but to a lesser degree. We also compared individual functional measures with histological outcomes such as lesion volume and neuronal cell loss across anatomical regions. In addition, we created a novel composite behavioral score index from individual complementary behavioral scores, and it provided superior discrimination across injury severities compared to individual tests. In summary, this study demonstrates the feasibility of using a larger number of complementary functional outcome behavioral tests than those traditionally employed to follow post-traumatic recovery after TBI, and suggests that the composite score may be a helpful tool for screening new neuroprotective agents or for addressing injury mechanisms.

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Section: Assessment Of Neuronal Cell Loss In the Hippocampal Sub-regionsmentioning

confidence: 99%

“…Lesion volume was determined based on the Cavalieri method as previously described. 33 The lesion area, including both the cavity and surrounding damaged tissue, was outlined using the Stereologer 2000 program (Systems Planning and Analysis, Alexandria, VA) to obtain the final volume measurements.…”

Section: Lesion Volume Assessmentmentioning

confidence: 99%

Comparing the Predictive Value of Multiple Cognitive, Affective, and Motor Tasks after Rodent Traumatic Brain Injury

Zhao

Loane

Murray

et al. 2012

Journal of Neurotrauma

102

140

View full text Add to dashboard Cite

show abstract

“…In addition, cyclin dependent kinase (CDK) inhibitors can reduce neuronal death, suppress reactive glia, and improve neurological outcomes in a number of acute and chronic neurodegenerative disorders [33,[35][36][37][38][39][40][41][42][43]. Little is known about the role of cell cycle genes in neuropathic pain.…”

Section: Introductionmentioning

confidence: 99%

Cell Cycle Activation Contributes to Increased Neuronal Activity in the Posterior Thalamic Nucleus and Associated Chronic Hyperesthesia after Rat Spinal Cord Contusion

Raver

Piao

et al. 2013

Neurotherapeutics

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Spinal cord injury (SCI) causes not only sensorimotor and cognitive deficits, but frequently also severe chronic pain that is difficult to treat (SCI pain). We previously showed that hyperesthesia, as well as spontaneous pain induced by electrolytic lesions in the rat spinothalamic tract, is associated with increased spontaneous and sensory-evoked activity in the posterior thalamic nucleus (PO). We have also demonstrated that rodent impact SCI increases cell cycle activation (CCA) in the injury region and that post-traumatic treatment with cyclin dependent kinase inhibitors reduces lesion volume and motor dysfunction. Here we examined whether CCA contributes to neuronal hyperexcitability of PO and hyperpathia after rat contusion SCI, as well as to microglial and astroglial activation (gliopathy) that has been implicated in delayed SCI pain. Trauma caused enhanced pain sensitivity, which developed weeks after injury and was correlated with increased PO neuronal activity. Increased CCA was found at the thoracic spinal lesion site, the lumbar dorsal horn, and the PO. Increased microglial activation and cysteine-cysteine chemokine ligand 21 expression was also observed in the PO after SCI. In vitro, neurons co-cultured with activated microglia showed up-regulation of cyclin D1 and cysteine-cysteine chemokine ligand 21 expression. In vivo, post-injury treatment with a selective cyclin dependent kinase inhibitor (CR8) significantly reduced cell cycle protein induction, microglial activation, and neuronal activity in the PO nucleus, as well as limiting chronic SCI-induced hyperpathia. These results suggest a mechanistic role for CCA in the development of SCI pain, through effects mediated in part by the PO nucleus. Moreover, cell cycle modulation may provide an effective therapeutic strategy to improve reduce both hyperpathia and motor dysfunction after SCI.

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“…2,3 Studies have demonstrated that TBI induces cell cycle activation (CCA) that may result in apoptosis of postmitotic cells (mature oligodendroglia and neurons) and activation of mitotic cells (microglia and astrocytes). [4][5][6][7][8][9] Microglial and astrocyte activation is associated with the release of proinflammatory molecules that can cause neurotoxicity. 5 Therefore, TBI-induced CCA may initiate multiple secondary injury mechanisms that directly and indirectly contribute to neuronal apoptosis and delayed neurotoxicity, respectively.…”

Section: Introductionmentioning

confidence: 99%

CR8, a Novel Inhibitor of CDK, Limits Microglial Activation, Astrocytosis, Neuronal Loss, and Neurologic Dysfunction after Experimental Traumatic Brain Injury

Kabadi

Stoica

Loane

et al. 2014

J Cereb Blood Flow Metab

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Central nervous system injury causes a marked increase in the expression of cell cycle-related proteins. In this study, we show that cell cycle activation (CCA) is detected in mature neurons at 24 hours after rat lateral fluid percussion (LFP)-induced traumatic brain injury (TBI), as reflected by increased expression of cyclin G1, phosphorylated retinoblastoma (phospho-Rb), E2F1 and proliferating cell nuclear antigen (PCNA). These changes were associated with progressive cortical, hippocampal, and thalamic neuronal loss and microglial and astrocyte activation. Notably, we detected 5-bromo-2 0 -deoxyuridine (BrdU)-positive neurons, microglia, and astrocytes at 7 days, but not at 24 hours, suggesting that cell cycle reaches the S phase in these cell types at the latter time point. A delayed systemic post-LFP administration at 3 hours of CR8-a potent second-generation cyclin-dependent kinase (CDK) inhibitor-reduced CCA; cortical, hippocampal, and thalamic neuronal loss; and cortical microglial and astrocyte activation. Furthermore, CR8 treatment attenuated sensorimotor and cognitive deficits, alleviated depressive-like symptoms, and decreased lesion volume. These findings underscore the contribution of CCA to progressive neurodegeneration and chronic neuroinflammation following TBI, and demonstrate the neuroprotective potential of cell cycle inhibition in a clinically relevant experimental TBI model.

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Selective CDK Inhibitor Limits Neuroinflammation and Progressive Neurodegeneration after Brain Trauma

Cited by 83 publications

References 46 publications

Comparing the Predictive Value of Multiple Cognitive, Affective, and Motor Tasks after Rodent Traumatic Brain Injury

Comparing the Predictive Value of Multiple Cognitive, Affective, and Motor Tasks after Rodent Traumatic Brain Injury

Cell Cycle Activation Contributes to Increased Neuronal Activity in the Posterior Thalamic Nucleus and Associated Chronic Hyperesthesia after Rat Spinal Cord Contusion

CR8, a Novel Inhibitor of CDK, Limits Microglial Activation, Astrocytosis, Neuronal Loss, and Neurologic Dysfunction after Experimental Traumatic Brain Injury

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