Major depressive disorder (MDD) is a common neuropsychiatric disorder affecting the mood and mental well-being. Its pathophysiology remains elusive due to the complexity and heterogeneity of this disorder that affects millions of individuals worldwide. Chronic stress is frequently cited as the one of the risk factors for MDD. To date, the conventional monoaminergic theory (serotonin, norepinephrine, and/or dopamine dysregulation) has received the most attention in the treatment of MDD, and all available classes of antidepressants target these monoaminergic systems. However, the contributions of other neurotransmitter systems in MDD have been widely reported. Emerging preclinical and clinical findings reveal that maladaptive glutamatergic neurotransmission might underlie the pathophysiology of MDD, thus revealing its critical role in the neurobiology of MDD and as the therapeutic target. Aiming beyond the monoaminergic hypothesis, studies of the neurobiological mechanisms underlying the stress-induced impairment of AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-glutamatergic neurotransmission in the brain could provide novel insights for the development of a new generation of antidepressants without the detrimental side effects. Here, the authors reviewed the recent literature focusing on the role of AMPA-glutamatergic neurotransmission in stress-induced maladaptive responses in emotional and mood-associated brain regions, including the hippocampus, amygdala, prefrontal cortex, nucleus accumbens and periaqueductal gray.

Background: Stroke is a common cause of disability and mortality worldwide; however, effective therapy remains limited. In stroke pathogenesis, ischemia/reperfusion injury triggers gliosis and neuroinflammation that further activates matrix metalloproteinases (MMPs), thereby damaging the blood–brain barrier (BBB). Increased BBB permeability promotes macrophage infiltration and brain edema, thereby worsening behavioral outcomes and prognosis. Histone deacetylase 1 (HDAC1) is a repressor of epigenomic gene transcription and participates in DNA damage and cell cycle regulation. Although HDAC1 is deregulated after stroke and is involved in neuronal loss and DNA repair, its role in neuroinflammation and BBB damage remains unknown. Methods: The rats with cerebral ischemia were evaluated in behavioral outcomes, levels of inflammation in gliosis and cytokines, and BBB damage by using an endothelin-1-induced rat model with cerebral ischemia/reperfusion injury. Results: The results revealed that HDAC1 dysfunction could promote BBB damage through the destruction of tight junction proteins, such as ZO-1 and occludin, after stroke in rats. HDAC1 inhibition also increased the levels of astrocyte and microglial gliosis, tumor necrosis factor-alpha, interleukin-1 beta, lactate dehydrogenase, and reactive oxygen species, further triggering MMP-2 and MMP-9 activity. Moreover, modified neurological severity scores for the cylinder test revealed that HDAC1 inhibition deteriorated behavioral outcomes in rats with cerebral ischemia. Discussion: HDAC1 plays a crucial role in ischemia/reperfusion-induced neuroinflammation and BBB damage, thus indicating its potential as a therapeutic target.

Stroke is a common cause of death worldwide and leads to disability and cognitive dysfunction. Ischemic stroke and hemorrhagic stroke are major categories of stroke, accounting for 68% and 32% of strokes, respectively. Each year, 15 million people experience stroke worldwide, and the stroke incidence is rising. Epigenetic modifications regulate gene transcription and play a major role in stroke. Accordingly, histone deacetylase 1 (HDAC1) participates in DNA damage repair and cell survival. However, the mechanisms underlying the role of HDAC1 in stroke pathogenesis are still controversial. Therefore, we investigated the role of HDAC1 in stroke by using a rat model of endothelin-1-induced brain ischemia. Our results revealed that HDAC1 was deregulated following stroke, and its expressional level and enzymatic activity were decreased. We also used MS-275 to inhibit HDAC1 function in rats exposed to ischemic insult. We found that HDAC1 inhibition promoted the infarct volume, neuronal loss, DNA damage, neuronal apoptosis after stroke, and levels of reactive oxygen species and inflammation cytokines. Additionally, HDAC1 inhibition deteriorated the behavioral outcomes of rats with ischemic insult. Overall, our findings demonstrate that HDAC1 participates in ischemic pathogenesis in the brain and possesses potential for use as a therapeutic target.

Polycystic ovary syndrome (PCOS) is the most common reproductive disease affecting the hormone and metabolic status of women. Its associated symptoms are diverse among the patients, including hyperandrogenism, insulin resistance, anovulation, infertility, obesity, hirsutism, acne, and more. In addition, PCOS can potentially increase the risk of dysmenorrhea, endometriosis, endometrioma, and irritable bowel syndrome, which are highly related to pelvic pain and sexual difficulty. However, little known is whether PCOS exacerbates other chronic bodily pain or contributes to hyperalgesia. Health-related quality of Life (HRQoL) reflects the life satisfaction and quality derived by an individual from mental, physical, emotional, and social activities under specific conditions. In this study, we reviewed pain perception from HRQoL of PCOS patients (SF-36). The review data evidently indicated that pain perception is significantly more prevalent in patients with PCOS than in healthy controls, and obesity and infertile status could be the rationales associated with pain development. Nevertheless, underlying causes remain undetermined due to the limited information from SF-36. Furthermore, we reviewed pathophysiologic factors to pain development or exacerbation, such as the deregulation of inflammation levels, adipokines, and insulin resistance. Although current evidence of pain perception and pathophysiologic risk factors are solid in PCOS, patients’ pain perception is often ignored in clinical settings. Clinicians should note the perception and treatment of pain in PCOS patients. The correlation or causality between pain and PCOS warrants further clinical examination and basic studies, thereby providing new insights into this topic in the context of clinical diagnosis and health care.

Introduction: Cerebral ischemia is a leading cause of disability and death worldwide. However, an effective therapeutic approach for the condition remains undiscovered. The previously proposed growth factor-based therapy has been inefficient due to its inability to pass through the blood–brain barrier. B355252, a newly developed small molecule, exhibited a potential neuroprotective effect in vivo. However, its exact efficacy in cerebral ischemia remains unclear. Methods: We adopt an endothelin-1 stereotaxic intracranial injection to induced cerebral ischemia in rat. We further conducted 2,3,5-triphenyltetrazolium chloride (TTC) staining, immunofluorescent staining, enzyme-linked immunosorbent assay (ELISA), and behavioral tests to evaluate the efficacy of B355252 in neuroprotection, anti-inflammation, and behavioral outcome improvements. Results: We identified that B355252 could protect ischemic neurons from neuronal loss by attenuating DNA damage, reducing ROS production and the LDH level, and preventing neuronal apoptosis. Moreover, inflammatory responses in astrocytic and microglial gliosis, as well as IL-1β and TNF-α levels, were ameliorated. Consequently, the behavioral outcomes of ischemic rats in neurologic responses and fore paw function recovery were improved. Discussion: Overall, our study verified the in vivo therapeutic potential of B355252. The study findings further support its application in the development of a therapeutic approach for stroke.

A therapeutic approach for promoting neuroprotection and brain functional regeneration after strokes is still lacking. Histone deacetylase 1 (HDAC1), which belongs to the histone deacetylase family, is involved in the transcriptional repression of cell-cycle-modulated genes and DNA damage repair during neurodegeneration. Our previous data showed that the protein level and enzymatic activity of HDAC1 are deregulated in stroke pathogenesis. A novel compound named 5104434 exhibits efficacy to selectively activate HDAC1 enzymatic function in neurodegeneration, but its potential in stroke therapy is still unknown. In this study, we adopted an induced rat model with cerebral ischemia using the vessel dilator endothelin-1 to evaluate the potential of compound 5104434. Our results indicated compound 5104434 selectively restored HDAC1 enzymatic activity after oxygen and glucose deprivation, preserved neurite morphology, and protected neurons from ischemic damage in vitro. In addition, compound 5104434 attenuated the infarct volume, neuronal loss, apoptosis, DNA damage, and DNA breaks in cerebral ischemia rats. It further ameliorated the behavioral outcomes of neuromuscular response, balance, forepaw strength, and functional recovery. Collectively, our data support the efficacy of compound 5104434 in stroke therapy and contend that it can be considered for clinical trial evaluation.