Cognitive Improvement by Vorinostat through Modulation of Endoplasmic Reticulum Stress in a Corticosterone-Induced Chronic Stress Model in Mice

Abstract

Chronic stress is the leading cause of memory impairment today. Various stress-based models are being developed for studying cognitive impairment. Repurposing of existing drugs in a new pharmacology class is the safest and cheapest option for treatment instead of new drug discovery. Vorinostat (VOR) is the first histone deacetylase (HDAC) inhibitor approved for the treatment of cutaneous T-cell lymphoma by the U.S. FDA. VOR follows the rule of five and is reported to cross the blood−brain barrier. Therefore, we aimed to evaluate the procognitive potential of VOR (25 mg/kg) administered by intraperitoneal (ip) route in a stress-based model of chronic corticosterone (CORT) injections (20 mg/kg, subcutaneously (sc)). The study comprised six groups. Normal mice were administered vehicle (VEH) (days 1−21, sc) in the first group, VOR (days 8−21, 25 mg/kg, ip) in the second group, and fluoxetine (FLX) (days 8−21, 15 mg/kg, oral) in the third group. Mice in the remaining three groups were given 20 mg/kg (sc) CORT for 21 days, and VOR (days 8−21, 25 mg/kg, ip) or FLX (days 8−21, 15 mg/kg, oral) was additionally administered to the treatment groups. Behavioral tests such as Morris water maze test, novel object recognition test, and object in place test were performed at the end of the dosing schedule to assess cognition. After behavior tests, mice were sacrificed, and hippocampus was separated from brain tissue for reverse transcriptase polymerase chain reaction (RT-PCR), Western blot, and immunohistochemistry studies. VOR treatment attenuated endoplasmic reticulum (ER) stress in CORT mice as evident from the reduction in DNA damage-inducible transcript 3 (Ddit3) (gene encoding CHOP), caspase 12 (Casp12), and calpain-2 (Capn2) mRNA levels, and cleaved caspase 3 (CASP3) protein expression. Bax inhibitor-1 (BI-1) was significantly increased in VOR-treated CORT mice. VOR also reversed CORT induced increase in HDAC2 level in the CA3 region. The protective effects of VOR were comparable to that of FLX in CORT mice. Thus, VOR has the potential to reverse cognitive dysfunction via modulation of ER stress markers and HDAC2.

Epigenetic Targeting of Histone Deacetylases in Diagnostics and Treatment of Depression

“…In addition to the antidepressant effect, HDAC inhibitors promoted neuronal rewiring and recovery of motor functions after traumatic brain injury [143]. Also, HDAC inhibitors such as sodium butyrate and SAHA enhanced cognitive function, which may provide therapeutic options for depression that accompanies cognitive impairment [144][145][146]. A recent drug repositioning study for precise/personalized medicine in depression using bioinformatic analyses revealed that HDAC inhibitors such as trichostatin A and valproic acid as a new potential antidepressant drug [117].…”

Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential

“…HDACis, such as sodium butyrate and SAHA, promote cognitive function, and may provide therapeutic options for depressed patients with cognitive impairment. 405 – 407 Although medications targeting these epigenetic molecules are proving effective in preclinical animal studies, there is a lack of successful clinical trials of HDACi in neuropsychiatric disorders, perhaps because of the complexity of different HDAC isoforms (i.e., HDAC2 and HDAC5) that are associated with pro-depressant and antidepressant functions. 408 The complexity is further heightened because HDAC and DNMT are widely distributed in the CNS and peripheral tissues.…”

Epigenetics 2.0: Special Issue on Epigenetics—Call for Papers

“…Recent work reported in ACS Chemical Neuroscience has demonstrated cognitive improvement stimulated by the HDAC inhibitor vorinostat, in a mouse model of chronic stress. 14 Powerful PET imaging tools that enable visualization of HDAC6 occupancy in vivo have also been reported recently. 15 Since our previous special issue, molecular investigations focusing on disease-related epigenetic processes in non-human species, including disease-causing parasites, are starting to emerge.…”