Calpain inhibitor inhibits p35-p25-Cdk5 activation, decreases tau hyperphosphorylation, and improves neurological function after spinal cord hemisection in rats

Kuo Sheng Hung, Shiuh Lin Hwang, Chung Ling Liang, Yann Jang Chen, Tsung Hsing Lee, Jong Kang Liu, Shen Long Howng, Cheng Haung Wang

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Aberrant calpain activation is a key mediator of neuron death. We examined the cell-permeable calpain inhibitor MDL28170 in the pathophysiological processes after spinal cord injury (SCI) including p35-p25- cyclin-dependent kinase-5 (Cdk5) activation, tau hyperphosphorylation, neuron cell death, calpain I activation, astrogliosis, and microglia activation. Our study showed that intrathecal administration of MDL28170 improved neurologic dysfunction, prevented neuron loss, decreased the number of apoptotic cells, and abated astrogliosis and microglia activation 7 days after spinal cord hemisection in rats. Reverse transcription polymerase chain reaction demonstrated calpain inhibition significantly attenuated the ratio of proapoptotic Bax/anti-apoptotic Bcl-2 mRNA in the lesion and penumbra after SCI. Calpain, the calcium-activated proteolytic enzyme, was found to digest p35 to its truncated product, p25. Moreover, abnormal Cdk5 activation by p25 and subsequent tau hyperphosphorylation triggers pathologic events leading to neurodegeneration and neurofibrillary tangles. We found p35-p25-Cdk5 activation and tau hyperphosphorylation in SCI, and then we showed that intrathecal MDL28170 treatment could diminish p35 truncation, and abrogate aberrant tau phosphorylation. Double labeling of calpain I and phosphorylated tau (AT8) in the same cells of spinal cord lesion further implicated pathogenesis of SCI. In conclusion, MDL28170 abated calpain I activation, inhibited apoptosis and neuron loss, quenched microglia and astrocyte activation, and significantly improved neurologic deficit one week after spinal cord hemisection. The neuroprotective mechanisms of calpain inhibitor in SCI could be attenuating upregulation of Bax/Bcl-2 ratio, preventing p35 truncation in the lesion and penumbra, and abrogating tau hyperphosphorylation.

Original languageEnglish
Pages (from-to)15-26
Number of pages12
JournalJournal of Neuropathology and Experimental Neurology
Volume64
Issue number1
Publication statusPublished - Jan 2005
Externally publishedYes

Fingerprint

Cyclin-Dependent Kinase 5
Calpain
Spinal Cord
Spinal Cord Injuries
Microglia
Neurons
Neurologic Manifestations
Neurofibrillary Tangles
Astrocytes
Reverse Transcription
calpain inhibitors
Peptide Hydrolases
Cell Death
Up-Regulation
Cell Count
Phosphorylation
Apoptosis
Calcium
Polymerase Chain Reaction
Messenger RNA

Keywords

  • Apoptosis
  • Calpain inhibitor
  • Hemisection
  • p35
  • Spinal cord injury
  • Tau

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neuroscience(all)

Cite this

Calpain inhibitor inhibits p35-p25-Cdk5 activation, decreases tau hyperphosphorylation, and improves neurological function after spinal cord hemisection in rats. / Hung, Kuo Sheng; Hwang, Shiuh Lin; Liang, Chung Ling; Chen, Yann Jang; Lee, Tsung Hsing; Liu, Jong Kang; Howng, Shen Long; Wang, Cheng Haung.

In: Journal of Neuropathology and Experimental Neurology, Vol. 64, No. 1, 01.2005, p. 15-26.

Research output: Contribution to journalArticle

Hung, Kuo Sheng ; Hwang, Shiuh Lin ; Liang, Chung Ling ; Chen, Yann Jang ; Lee, Tsung Hsing ; Liu, Jong Kang ; Howng, Shen Long ; Wang, Cheng Haung. / Calpain inhibitor inhibits p35-p25-Cdk5 activation, decreases tau hyperphosphorylation, and improves neurological function after spinal cord hemisection in rats. In: Journal of Neuropathology and Experimental Neurology. 2005 ; Vol. 64, No. 1. pp. 15-26.
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