Effects of Veliparib on Microglial Activation and Functional Outcomes after Traumatic Brain Injury in the Rat and Pig
| Autor: | S. Scott Panter, Seok Joon Won, Giordano Fabricio Cittolin-Santos, Robin K Bishop, Eric Rome, Karen-Amanda Irvine, Jayinee Basu, Jianguo Xu, Raymond A. Swanson, Katherine A. Hamel, Andrew Sondag, Valerie G. Coppes, Pardeep Singh |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
IL1-ß Programmed cell death Veliparib Traumatic brain injury Clinical Sciences Axonal loss Inflammation Neurodegenerative Pharmacology Corpus callosum axonal injury Lesion 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine TNFα medicine 2.1 Biological and endogenous factors Aetiology Neurology & Neurosurgery MMP9 business.industry Dentate gyrus Rehabilitation Neurosciences medicine.disease Brain Disorders 030104 developmental biology chemistry Injury (total) Accidents/Adverse Effects Neurology (clinical) medicine.symptom business TNF alpha IL1-beta 030217 neurology & neurosurgery |
| Zdroj: | Journal of neurotrauma, vol 35, iss 7 |
| ISSN: | 1557-9042 0897-7151 |
| DOI: | 10.1089/neu.2017.5044 |
| Popis: | The inflammation response induced by brain trauma can impair recovery. This response requires several hours to develop fully and thus provides a clinically relevant therapeutic window of opportunity. Poly(ADP-ribose) polymerase inhibitors suppress inflammatory responses, including brain microglial activation. We evaluated delayed treatment with veliparib, a poly(ADP-ribose) polymerase inhibitor, currently in clinical trials as a cancer therapeutic, in rats and pigs subjected to controlled cortical impact (CCI). In rats, CCI induced a robust inflammatory response at the lesion margins, scattered cell death in the dentate gyrus, and a delayed, progressive loss of corpus callosum axons. Pre-determined measures of cognitive and motor function showed evidence of attentional deficits that resolved after three weeks and motor deficits that recovered only partially over eight weeks. Veliparib was administered beginning 2 or 24 h after CCI and continued for up to 12 days. Veliparib suppressed CCI-induced microglial activation at doses of 3 mg/kg or higher and reduced reactive astrocytosis and cell death in the dentate gyrus, but had no significant effect on delayed axonal loss or functional recovery. In pigs, CCI similarly induced a perilesional microglial activation that was attenuated by veliparib. CCI in the pig did not, however, induce detectable persisting cognitive or motor impairment. Our results showed veliparib suppression of CCI-induced microglial activation with a delay-to-treatment interval of at least 24 h in both rats and pigs, but with no associated functional improvement. The lack of improvement in long-term recovery underscores the complexities in translating anti-inflammatory effects to clinically relevant outcomes. |
| Databáze: | OpenAIRE |
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