Intranasal Delivery of a Caspase-1 Inhibitor in the Treatment of Global Cerebral Ischemia

Ningjun Zhao, Xiaoying Zhuo, Yujiao Lu, Yan Dong, Mohammad Ejaz Ahmed, Donovan Tucker, Erin L. Scott, Quanguang Zhang

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4936-4952
Number of pages17
JournalMolecular Neurobiology
Volume54
Issue number7
DOIs
StatePublished - Sep 1 2017

Fingerprint

Brain Ischemia
Caspase 1
Hippocampal CA1 Region
Intranasal Administration
Transient Ischemic Attack
Reactive Inhibition
Gliosis
Long-Term Memory
In Situ Nick-End Labeling
Neuroprotective Agents
Therapeutics
Caspase 3
Anti-Inflammatory Agents
Ischemia
Central Nervous System
Pharmacology
Cytokines
Efficiency
interleukin-1beta-converting enzyme inhibitor
Wounds and Injuries

Keywords

  • Cardiac arrest
  • Functional improvements
  • Gliosis
  • Mitochondria
  • Neuroprotection

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

Intranasal Delivery of a Caspase-1 Inhibitor in the Treatment of Global Cerebral Ischemia. / Zhao, Ningjun; Zhuo, Xiaoying; Lu, Yujiao; Dong, Yan; Ahmed, Mohammad Ejaz; Tucker, Donovan; Scott, Erin L.; Zhang, Quanguang.

In: Molecular Neurobiology, Vol. 54, No. 7, 01.09.2017, p. 4936-4952.

Research output: Contribution to journalArticle

Zhao, N, Zhuo, X, Lu, Y, Dong, Y, Ahmed, ME, Tucker, D, Scott, EL & Zhang, Q 2017, 'Intranasal Delivery of a Caspase-1 Inhibitor in the Treatment of Global Cerebral Ischemia', Molecular Neurobiology, vol. 54, no. 7, pp. 4936-4952. https://doi.org/10.1007/s12035-016-0034-9
Zhao, Ningjun ; Zhuo, Xiaoying ; Lu, Yujiao ; Dong, Yan ; Ahmed, Mohammad Ejaz ; Tucker, Donovan ; Scott, Erin L. ; Zhang, Quanguang. / Intranasal Delivery of a Caspase-1 Inhibitor in the Treatment of Global Cerebral Ischemia. In: Molecular Neurobiology. 2017 ; Vol. 54, No. 7. pp. 4936-4952.
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