panobinostat and givinostat

Chronic triptan exposure in rodents recapitulates medication overuse headache (MOH), causing cephalic pain sensitization and trigeminal ganglion overexpression of pronociceptive proteins including CGRP. Because of these transcriptional derangements, as well as the emerging role of epigenetics in chronic pain, in the present study, we evaluated the effects of the histone deacetylase inhibitors (HDACis) panobinostat and givinostat, in rats chronically exposed to eletriptan for 1 month. Both panobinostat and givinostat counteracted overexpression of genes coding for CGRP and its receptor subunit RAMP1, having no effects on CLR and RCP receptor subunits in the trigeminal ganglion (TG) of eletriptan-exposed rats. Within the trigeminal nucleus caudalis (TNc), transcripts for these genes were neither upregulated by eletriptan nor altered by concomitant treatment with panobinostat or givinostat. HDACis counteracted hypersensitivity to capsaicin-induced vasodilatation in the trigeminal territory, as well as photophobic behavior and cephalic allodyniain eletriptan-exposed rats. Eletriptan did not affect CGRP, CLR, and RAMP1 expression in cultured trigeminal ganglia, whereas both inhibitors reduced transcripts for CLR and RAMP-1. The drugs, however, increased luciferase expression driven by CGRP promoter in cultured cells. Our findings provide evidence for a key role of HDACs and epigenetics in MOH pathogenesis, highlighting the therapeutic potential of HDAC inhibition in the prevention of migraine chronification. PERSPECTIVE: The present study highlights a key epigenetic role of HDAC in the rodent model of medication overuse headache, furthering our understanding of the molecular mechanisms responsible for pronociceptive sensitization during headache chronification.

Topics: Animals; Calcitonin Gene-Related Peptide; Headache; Headache Disorders, Secondary; Histone Deacetylase Inhibitors; Panobinostat; Rats; Trigeminal Ganglion

Acute gouty arthritis is caused by endogenously formed monosodium urate (MSU) crystals, which are potent activators of the NLRP3 inflammasome. However, to induce the release of active interleukin (IL)-1β, an additional stimulus is needed. Saturated long-chain free fatty acids (FFAs) can provide such a signal and stimulate transcription of pro-IL-1β. In contrast, the short-chain fatty acid butyrate possesses anti-inflammatory effects. One of the mechanisms involved is inhibition of histone deacetylases (HDACs). Here, we explored the effects of butyrate on MSU+FFA-induced cytokine production and its inhibition of specific HDACs.. Freshly isolated peripheral blood mononuclear cells (PBMCs) from healthy donors were stimulated with MSU and palmitic acid (C16.0) in the presence or absence of butyrate or a synthetic HDAC inhibitor. Cytokine responses were measured with ELISA and quantitative PCR. HDAC activity was measured with fluorimetric assays.. Butyrate decreased C16.0+MSU-induced production of IL-1β, IL-6, IL-8 and IL-1β mRNA in PBMCs from healthy donors. Similar results were obtained in PBMCs isolated from patients with gout. Butyrate specifically inhibited class I HDACs. The HDAC inhibitor, panobinostat and the potent HDAC inhibitor, ITF-B, also decreased ex vivo C16.0+MSU-induced IL-1β production.. In agreement with the reported low inhibitory potency of butyrate, a high concentration was needed for cytokine suppression, whereas synthetic HDAC inhibitors showed potent anti-inflammatory effects at nanomolar concentrations. These novel HDAC inhibitors could be effective in the treatment of acute gout. Moreover, the use of specific HDAC inhibitors could even improve the efficacy and reduce any potential adverse effects.

Topics: Adult; Antioxidants; Arthritis, Gouty; Butyrates; Carbamates; Crystallization; Cytokines; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Female; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Indoles; Interleukin-1beta; Interleukin-6; Interleukin-8; Leukocytes, Mononuclear; Male; Middle Aged; Palmitic Acid; Panobinostat; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Uric Acid