J Korean Neurosurg Soc.  2012 Apr;51(4):191-198. 10.3340/jkns.2012.51.4.191.

The Neuroprotective Effect of Treatment of Valproic Acid in Acute Spinal Cord Injury

• Yu SH
• Cho DC
• Kim KT
• Nam KH
• Cho HJ
• Sung JK

• KMID: 2066909
• DOI: http://doi.org/10.3340/jkns.2012.51.4.191

Abstract

OBJECTIVE
Valproic acid (VPA), as known as histone deacetylase inhibitor, has neuroprotective effects. This study investigated the histological changes and functional recovery from spinal cord injury (SCI) associated with VPA treatment in a rat model.
METHODS
Locomotor function was assessed according to the Basso-Beattie-Bresnahan scale for 2 weeks in rats after receiving twice daily intraperitoneal injections of 200 mg/kg VPA or the equivalent volume of normal saline for 7 days following SCI. The injured spinal cord was then examined histologically, including quantification of cavitation.
RESULTS
Basso-Beattie-Bresnahan scale scores in rats receiving VPA were significantly higher than in the saline group (p<0.05). The cavity volume in the VPA group was significantly reduced compared with the control (saline-injected) group (p<0.05). The level of histone acetylation recovered in the VPA group, while it was significantly decreased in the control rats (p<0.05). The macrophage level was significantly decreased in the VPA group (p<0.05).
CONCLUSION
VPA influences the restoration of hyperacetylation and reduction of the inflammatory reaction resulting from SCI, and is effective for histology and motor function recovery.

Keyword

Valproic acid; Spinal cord injury; Clip compression model; Acetylation; HDAC inhibitor

MeSH Terms

Acetylation
Animals
Histone Deacetylase Inhibitors
Histones
Injections, Intraperitoneal
Macrophages
Neuroprotective Agents
Rats
Recovery of Function
Spinal Cord
Spinal Cord Injuries
Valproic Acid
Histone Deacetylase Inhibitors
Histones
Neuroprotective Agents
Valproic Acid

Figure

• 

  Fig. 1 Neurological function of rats after SCI between VPA- and saline-injected groups, assessed by the BBB locomotor rating scale. VPA improved functional recovery after SCI. The error bars indicate the SEM. *p<0.05 on 7, 10, and 14 day (n=12/group). SCI : spinal cord injury, VPA : valproic acid, SEM : standard error of the mean, BBB : Basso, Beattie, and Bresnahan.

• 

  Fig. 2 Representative spinal cord sections stained with hematoxylin and eosin showing the cavities at 2 weeks after T9 clip compression injury taken at the epicenter and at 2 mm increments rostral and caudal in a rat receiving saline vehicle and a rat treated five times with valproic acid (VPA). Larger cavitation is evident in saline-injected group than the VPA-injected group, a progressive diminishment with distance from the epicenter of the lesion. Scale bar=500 µm; 5× magnification. SCI : spinal cord injury.

• 

  Fig. 3 VPA improves spinal cord tissue sparing after SCI. A : Measurements of the average area of preserved cord tissues at the injury epicenter and adjacent sections at an interval of 2 mm up to 6 mm rostrally and caudally. B : Histogram showing the cavitation volume of the spinal cord lesion in both groups. There was a considerable reduction of the cavity volumes in the VPA-treated group compared to the saline-injected group. The error bars indicate SEM. *p<0.05 for VPA-injected groups vs. saline-injected groups after SCI. R : rostral, C : caudal (n=6/group), SCI : spinal cord injury, VPA : valproic acid, SEM : standard error of the mean.

• 

  Fig. 4 Representative photographs of histone acetylation immunoreactive cells from SCI to sham animals at 6 mm both rostral and caudal to the lesion epicenter, 40×. There is a significantly restoration of the immunoreactivity of histone acetylation at both white and gray matter in VPA-injected group while in saline-injected groups, there are hyperacetylation at both white and gray matter. Scale bar=50 µm; 40× magnification. SCI : spinal cord injury, VPA : valproic acid.

• 

  Fig. 5 Histogram of the quantification of the histone acetylation immunoreactive cells showing that VPA treatment increases the number of histone acetylation immunoreactive cells at 6 mm both rostral and caudal to the lesion epicenter. A : Acetyl-histon H3/K9. B : Acetyl-histon H3/K18. The error bars indicate SEM. *p<0.05 (n=6/group). SCI : spinal cord injury, VPA : valproic acid, SEM : standard error of the mean.

• 

  Fig. 6 Representative photographs of ED-1 immunoreactive cells from SCI to sham animals at 6 mm both rostral and caudal to the lesion epicenter, 40×. Considerable decline of the immunoreactivity of ED-1 is evident in both white and gray matter in VPA-injected groups, while in saline-injected groups high immunoreactivity of ED-1 is evident. Scale bar=50 µm; 40× magnification. SCI : spinal cord injury, VPA : valproic acid.

• 

  Fig. 7 Histogram of the quantification of the ED-1 immunoreactive cells showing that VPA treatment decreases the number of ED-1 immunoreactive cells at 6 mm both rostral and caudal to the lesion epicenter. The error bars indicate SEM. *p<0.05 (n=6/group). SCI : spinal cord injury, VPA : valproic acid, SEM : standard error of the mean.

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