The new HDAC1 inhibitor LG325 ameliorates neuropathic pain in a mouse model.

Abstract

Current analgesic therapies for treatment of neuropathic pain are unsatisfactory. Neuropathic pain is, therefore, undertreated and there is a significant need for a better pharmacotherapy. Increasing evidence indicate that histone deacetylation is a critical step in nerve injury pain. To obtain an innovative treatment for the management of neuropathic pain, we investigated the pharmacological effects produced by the new histone deacetylase (HDAC)-1 selective inhibitor, LG325, in a mouse model of trauma-induced peripheral mononeuropathy provoked by spared nerve injury (SNI). LG325 dose-dependently ameliorated the mechanical allodynia of SNI mice with a prolonged effect that was still significant 150min after administration. The intensity of the antiallodynic effect was comparable to that produced by pregabalin and morphine, used as analgesic reference drugs. Conversely, The HDAC1-HDAC6 inhibitor LG322, used as structurally-related reference compound, showed a less favourable antinociceptive profile. The antihyperalgesic activity of LG325 was devoid of any alteration in animals' gross behaviour and did not impair locomotor activity at the highest effective dose. SNI mice showed a significant increase in the HDAC1 protein levels within spinal cord in coincidence with the nociceptive phenotype. Treatment with LG325 completely reversed the increased expression of HDAC1. These data illustrate the antihyperalgesic efficacy of LG325 indicating that selectively targeting HDAC1 could have promising therapeutic potential for neuropathic pain management.

• Authors: Maria Domenica Sanna, Luca Guandalini, Maria Novella Romanelli, Nicoletta Galeotti
• Journal: Pharmacology, biochemistry, and behavior (Pharmacol Biochem Behav) Vol. 160 Pg. 70-75 (09 2017) ISSN: 1873-5177 [Electronic] United States
• PMID: 28821396 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• Amides
• Histone Deacetylase Inhibitors
• LG325
• Benzodiazepines

Topics

• Amides (chemistry, pharmacology)
• Animals
• Behavior, Animal (drug effects)
• Benzodiazepines (chemistry, pharmacology)
• Disease Models, Animal
• Histone Deacetylase Inhibitors (pharmacology)
• Hyperalgesia (physiopathology)
• Locomotion (drug effects)
• Male
• Mice
• Neuralgia (prevention & control)