title: Intranasal Delivery of a Caspase-1 Inhibitor in the Treatment of Global Cerebral Ischemia.
abstract: Caspase-1 is an enzyme implicated in neuroinflammation, a critical component of many diseases that affect neuronal degeneration. However, it is unknown whether a caspase-1 inhibitor can modify apoptotic neuronal damage incurred during transient global cerebral ischemia (GCI) and whether intranasal administration of a caspase-1 inhibitor is an effective treatment following GCI. The present study was conducted to examine the potential efficiency of post-ischemic intranasal administration of the caspase-1 inhibitor Boc-D-CMK in a 4-vessel occlusion model of GCI in the rat. Herein, we show that intranasal Boc-D-CMK readily penetrated the central nervous system, subsequently inhibiting caspase-1 activity, decreasing mitochondrial dysfunction, and attenuating caspase-3-dependent apoptotic pathway in ischemia-vulnerable hippocampal CA1 region. Further investigation regarding the mechanisms underlying Boc-D-CMK's neuroprotective effects revealed marked inhibition of reactive gliosis, as well as reduction of the neuroinflammatory response via inhibition of the downstream pro-inflammatory cytokine production. Intranasal Boc-D-CMK post-treatment also significantly enhanced the numbers of NeuN-positive cells while simultaneously decreasing the numbers of TUNEL-positive and PARP1-positive cells in hippocampal CA1. Correspondingly, behavioral tests showed that deteriorations in spatial learning and memory performance, and long-term recognition memory following GCI were significantly improved in the Boc-D-CMK post-treated animals. In summary, the current study demonstrates that the caspase-1 inhibitor Boc-D-CMK coordinates anti-inflammatory and anti-apoptotic actions to attenuate neuronal death in the hippocampal CA1 region following GCI. Furthermore, our data suggest that pharmacological inhibition of caspase-1 is a promising neuroprotective strategy to target ischemic neuronal injury and functional deficits following transient GCI.
authors: Department of Emergency Medicine, Xuzhou Medical University, and Laboratory of Emergency Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, China.|Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, CA3050, Augusta, GA, 30912, USA.
authors: Ningjun
authors: N
authors: Zhao
authors: Department of Emergency Medicine, Xuzhou Medical University, and Laboratory of Emergency Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221002, China.|Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, CA3050, Augusta, GA, 30912, USA.
authors: Xiaoying
authors: X
authors: Zhuo
authors: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, CA3050, Augusta, GA, 30912, USA.
authors: Yujiao
authors: Y
authors: Lu
authors: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, CA3050, Augusta, GA, 30912, USA.
authors: Yan
authors: Y
authors: Dong
authors: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, CA3050, Augusta, GA, 30912, USA.
authors: Mohammad Ejaz
authors: ME
authors: Ahmed
authors: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, CA3050, Augusta, GA, 30912, USA.
authors: Donovan
authors: D
authors: Tucker
authors: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, CA3050, Augusta, GA, 30912, USA.
authors: Erin L
authors: EL
authors: Scott
authors: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, 1120 15th Street, CA3050, Augusta, GA, 30912, USA. qzhang@augusta.edu.
authors: Quanguang
authors: Q
authors: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D002544:Cerebral Infarction / Q000188:drug therapy*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology; D017207:Rats, Sprague-Dawley
chemical_list: D061945:Caspase Inhibitors; D018696:Neuroprotective Agents; C505410:Casp3 protein, rat; D053148:Caspase 3; D020170:Caspase 1
keywords: Cardiac arrest; Functional improvements; Gliosis; Mitochondria; Neuroprotection