Bcl-2 pathway inhibition in solid tumors: a review of clinical trials

Due to their key role in the pathogenesis of cancer through the regulation of apoptosis, the B-cell leukemia/lymphoma-2 (BCL-2) family proteins have been an attractive target for cancer therapy for the past decades. Throughout the years, many Bcl-2 family inhibitors have been developed, with Venetoclax being now successfully used in treating hematological malignancies. Although their effectiveness in the treatment of solid tumors is yet to be established, some preclinical evidence indicates their possible clinical application. This review aims to summarize current data from completed clinical trials that used Bcl-2 protein family inhibitors as monotherapy or in combination with other agents for the treatment of solid malignancies. We managed to include clinical trials of various phases which analyze the pharmacokinetics and pharmacodynamics of the drugs, as well as the effectiveness and adverse effects. Active and recruiting clinical trials are also briefly presented and future prospects and challenges are discussed (AU)

Safety of mirogabalin and pregabalin in Japanese patients with neuropathic pain: a retrospective cohort study.

BACKGROUND: Few studies have compared the safety risks between the gabapentinoids, pregabalin, and mirogabalin in post-marketing clinical settings. We assessed reported events associated with gabapentinoid use in patients with neuropathic pain. RESEARCH DESIGN AND METHODS: We conducted a retrospective cohort study between September 2020 and December 2020 using the community pharmacies records in Japan. The pharmacists identified new vs. prevalent users of mirogabalin and pregabalin in September 2020 and reported data regarding baseline and adverse events to the Japan Pharmaceutical Association using web-based questionnaires. The incidence of events and hazard ratio (HR) were consequently compared. RESULTS: New users of mirogabalin and pregabalin were identified (n = 1,650 and 2,244; mean age (SD): 69 (15) and 68 (16) years; women: 59% and 56%, respectively). Although serious events were not reported, a marked difference in HRs of common adverse events, including somnolence (1.6), dizziness (1.3), nausea (2.8), edema (3.1), and acetaminophen (2.0)/antidepressant (2.4) addition, was observed. CONCLUSION: No new serious safety concerns were found for mirogabalin and pregabalin use in patients with neuropathic pain, although the HR of some events indicated increased risk among mirogabalin users. However, further studies are needed as estimates for events occurring in small numbers with wide confidence intervals.

Relationship between the dose titration and adherence of mirogabalin in patients with peripheral neuropathic pain depending on renal function: a nationwide electronic medical record database study.

BACKGROUND: Mirogabalin has been attracting attention for treating peripheral neuropathic pain. The package insert recommends that mirogabalin should be titrated depending on renal function. Here, we investigated the relationship between dose titration patterns and adherence, and persistence of mirogabalin treatment. RESEARCH DESIGN AND METHODS: Peripheral neuropathic pain patients who initiated mirogabalin between March 2020 and May 2021 were identified using an electronic medical record database. The dose titration pattern was described according to degrees of renal function. Regression analyses were performed to compare adherence and persistence between the patients with and without titration. RESULTS: Of the 4,138 identified patients, 1,696 (41.0%) titrated the dose within 45 days and were more adherent than those without titration (Adjusted odds ratio: 1.75, 95% CI 1.21, 2.54). Of the total 952 patients with renal function parameters, 229 (24.1%) titrated to the effective dose within 45 days and were less likely to discontinue than those without titration (Adjusted hazard ratio: 0.57, 95% CI 0.40, 0.81). CONCLUSION: Mirogabalin dose titration was associated with better adherence and persistence. It is important for mirogabalin treatment to determine the initial prescription dose based on renal function and subsequent dose titration according to the package insert. TRIAL REGISTRATION: UMIN000047313.

Prophylactic effects of hyperforin on anhedonia-like phenotype in chronic restrain stress model: A role of gut microbiota.

Anhedonia is the core symptom of depression, which largely reflects the therapeutic effect of depression. Hypericum perforatum is one of the most important antidepressant herb that has fewer side effects than traditional antidepressants. Considering the antibacterial effect of Hypericum perforatum, we verified whether this antidepressant activity was related to intestinal microbiomics. So we established anhedonia mouse model to explore the underlying treatment mechanism of hyperforin, the key antidepressant ingredient of Hypericum perforatum and to screen new psychobiotics based on hyperforin. It was found that hyperforin prevented anhedonia induced by chronic restraint stress in mice and altered the richness and evenness of bacteria populations compared with stressed mice. Metastat analysis showed that Akkermansia muciniphila and Muribaculum intestinale were the bacterial species obviously affected by hyperforin, and their abundance in hyperforin-treated group significantly increased. The results suggest that the effect of hyperforin on anhedonia may be partly assisted by Akkermansia muciniphila. These also indicate that Muribaculum intestinale may be another important intestinal bacteria involved in the pathogenesis of anhedonia symptom and depression.

Mirogabalin vs pregabalin for chemotherapy-induced peripheral neuropathy in pancreatic cancer patients.

BACKGROUND: The prognosis of pancreatic cancer (PC) has been improved by new chemotherapy regimens (combination of 5-fluorouracil, oxaliplatin, irinotecan, and leucovorin (FOLFIRINOX) or gemcitabine plus nab-paclitaxel (GnP)). Unfortunately, chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse event of these two regimens. The efficacy of pregabalin for CIPN has been reported in previous studies. However, the efficacy of mirogabalin for CIPN remains unknown. Thus, in this study, we aimed to clarify which drug (mirogabalin or pregabalin) was more valuable for improving CIPN. METHODS: A total of 163 PC patients who underwent FOLFIRINOX or GnP between May 2014 and January 2021 were enrolled. Among them, 34 patients were diagnosed with CIPN. Thirteen patients were treated with mirogabalin (mirogabalin group), and twenty-one patients were treated with pregabalin (pregabalin group). Treatment efficacy was compared between the two groups. RESULTS: In both the mirogabalin group and the pregabalin group, the grade of patients with CIPN at 2, 4, and 6 weeks after the initiation of treatment showed significant improvement compared to the pretreatment grade. Notably, the rate of CIPN improvement was higher in the mirogabalin group than in the pregabalin group (2 weeks: 84.6% (11/13) vs 33.3% (7/21), P value = 0.005; 4 weeks, 6 weeks: 92.3% (12/13) vs 33.3% (7/21), P value = 0.001). CONCLUSIONS: Although both mirogabalin and pregabalin were effective at improving CIPN, mirogabalin might be a suitable first choice for CIPN in PC patients. TRIAL REGISTRATION: Not applicable.

Pretreatment with High Mobility Group Box-1 Monoclonal Antibody Prevents the Onset of Trigeminal Neuropathy in Mice with a Distal Infraorbital Nerve Chronic Constriction Injury.

Persistent pain following orofacial surgery is not uncommon. High mobility group box 1 (HMGB1), an alarmin, is released by peripheral immune cells following nerve injury and could be related to pain associated with trigeminal nerve injury. Distal infraorbital nerve chronic constriction injury (dIoN-CCI) evokes pain-related behaviors including increased facial grooming and hyper-responsiveness to acetone (cutaneous cooling) after dIoN-CCI surgery in mice. In addition, dIoN-CCI mice developed conditioned place preference to mirogabalin, suggesting increased neuropathic pain-related aversion. Treatment of the infraorbital nerve with neutralizing antibody HMGB1 (anti-HMGB1 nAb) before dIoN-CCI prevented both facial grooming and hyper-responsiveness to cooling. Pretreatment with anti-HMGB1 nAb also blocked immune cell activation associated with trigeminal nerve injury including the accumulation of macrophage around the injured IoN and increased microglia activation in the ipsilateral spinal trigeminal nucleus caudalis. The current findings demonstrated that blocking of HMGB1 prior to nerve injury prevents the onset of pain-related behaviors, possibly through blocking the activation of immune cells associated with the nerve injury, both within the CNS and on peripheral nerves. The current findings further suggest that blocking HMGB1 before tissue injury could be a novel strategy to prevent the induction of chronic pain following orofacial surgeries.

Ferula L. Plant Extracts and Dose-Dependent Activity of Natural Sesquiterpene Ferutinin: From Antioxidant Potential to Cytotoxic Effects.

The employment studies of natural extracts in the prevention and treatment of several diseases highlighted the role of different species of genus Ferula L., belonging to the Apiaceae family, dicotyledonous plants present in many temperate zones of our planet. Ferula communis L. is the main source of sesquiterpene ferutinin, a bioactive compound studied both in vitro and in vivo, because of different effects, such as phytoestrogenic, antioxidant, anti-inflammatory, but also antiproliferative and cytotoxic activity, performed in a dose-dependent and cell-dependent way. The present review will focus on the molecular mechanisms involved in the different activities of Ferutinin, starting from its antioxidant potential at low doses until its ionophoric property and the subsequent mitochondrial dysfunction induced through administration of high doses, which represent the key point of its anticancer action. Furthermore, we will summarize the data acquired from some experimental studies on different cell types and on several diseases. The results obtained showed an important antioxidant and phytoestrogenic regulation with lack of typical side effects related to estrogenic therapy. The preferential cell death induction for tumor cell lines suggests that ferutinin may have anti-neoplastic properties, and may be used as an antiproliferative and cytotoxic agent in an estrogen dependent and independent manner. Nevertheless, more data are needed to clearly understand the effect of ferutinin in animals before using it as a phytoestrogen or anticancer drug.

Long-term safety and efficacy of mirogabalin in Asian patients with postherpetic neuralgia: Results from an open-label extension of a multicenter randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Postherpetic neuralgia (PHN) is a condition that results from nerve dysfunction following an episode of acute herpes zoster (shingles). Mirogabalin is a novel, selective oral α2δ ligand that demonstrated safety and efficacy in a multicenter, randomized, double-blind, placebo-controlled 14-week study in Asian patients with PHN. This 52-week, open-label extension study investigated the long-term safety and efficacy of flexible-dosage mirogabalin in Asian patients with PHN. METHODS: This open-label extension study enrolled patients who completed the placebo-controlled study. Patients started with a dose of 5 mg mirogabalin twice daily (BID), which was followed by a flexible dose of 10 or 15 mg BID. During the study, patients assessed their pain using the Short-Form McGill Pain Questionnaire (SF-MPQ). Adverse events were monitored throughout the study. RESULTS: Of 239 enrolled patients, 184 (77.0%) completed the study and 185 patients (77.4%) received the 15 mg BID dose most during the treatment duration. Most treatment-emergent adverse events (TEAEs) were mild or moderate. The most common TEAEs were nasopharyngitis, somnolence, dizziness, weight increased, and edema. All SF-MPQ scales decreased from baseline to week 52. CONCLUSIONS: This study showed the safety and stable pain management of a long-term flexible dosing regimen of mirogabalin 10 or 15 mg twice daily for 52 weeks in patients with PHN. CLINICAL TRIAL REGISTERED AT CLINICALTRIALS.GOV:: NCT02318719. SUMMARY FOR TABLE OF CONTENTS: Mirogabalin-a novel α2δ oral ligand-was shown to be effective and well tolerated for treating postherpetic neuralgia (PHN) in an Asian multicenter, randomized, double-blind, placebo-controlled, 14-week study. This open-label, 52-week study was conducted as an extension of the double-blind study to demonstrate long-term safety and efficacy of mirogabalin.

[Analgesic Effects of Mirogabalin for Cancer Pain].

Mirogabalin is a novel drug for alleviating peripheral neuropathic pain, available since April 2019 in Japan. Since cancer pain was not included as an outcome in clinical trials for product approval, there have been no reports on its effectiveness or safety for treating cancer pain. The purpose of this study was to evaluate the effectiveness and safety of mirogabalin for patients with cancer pain. During the 5 months from April to August 2019, our palliative care team prescribed mirogabalin to 34 patients who had not achieved effective analgesia even after opioid titration. Effectiveness was defined as(1)reduction in persistent pain of 50% or more on the numeric rating scale(NRS); or(2)reduction in the frequency of rescue medicine of 50% or more for breakthrough pain. Based on this definition, the rate of effectiveness of mirogabalin was 88.2%. Two patients experienced mild side effects in the central nervous system. However, these effects did not result in discontinuation of the medication. The results of the study showed that mirogabalin can be used effectively and safely for cancer pain relief.

Pharmacological Inhibition of Soluble Epoxide Hydrolase as a New Therapy for Alzheimer's Disease.

The inhibition of the enzyme soluble epoxide hydrolase (sEH) has demonstrated clinical therapeutic effects in several peripheral inflammatory-related diseases, with 3 compounds in clinical trials. However, the role of this enzyme in the neuroinflammation process has been largely neglected. Herein, we disclose the pharmacological validation of sEH as a novel target for the treatment of Alzheimer's disease (AD). Evaluation of cognitive impairment and pathological hallmarks were used in 2 models of age-related cognitive decline and AD using 3 structurally different and potent sEH inhibitors as chemical probes. sEH is upregulated in brains from AD patients. Our findings supported the beneficial effects of central sEH inhibition, regarding reducing cognitive impairment, neuroinflammation, tau hyperphosphorylation pathology, and the number of amyloid plaques. This study suggests that inhibition of inflammation in the brain by targeting sEH is a relevant therapeutic strategy for AD.

Short-term outcomes of mirogabalin in patients with peripheral neuropathic pain: a retrospective study.

BACKGROUND: Mirogabalin, which is approved for the treatment of peripheral neuropathic pain in Japan, is a ligand for the α2δ subunit of voltage-gated calcium channels. Both pregabalin and mirogabalin act as nonselective ligands at the α2δ-1 and α2δ-2 subunits. Mirogabalin has a unique binding profile and long duration of action. Pregabalin has been reported to produce intolerable adverse effects in some patients. This study investigated outcomes associated with mirogabalin administration in patients with peripheral neuropathic pain who ceased treatment with pregabalin. METHODS: We retrospectively assessed peripheral neuropathic pain using the neuropathic pain screening questionnaire (NeP score) in 187 patients (58 men, 129 women) who were treated with mirogabalin. All patients had switched from pregabalin to mirogabalin due to lack of efficacy or adverse events. Differences in the treatment course (i.e., numeric rating scale (NRS) scores) were compared using one-way analysis of variance with Bonferroni post hoc tests. RESULTS: The mean age of the patients was 72.3 years (range, 30-94 years), and the mean duration of disease was 37 months (range, 3-252 months). After treatment with mirogabalin for 1 week, NRS scores significantly decreased compared with baseline and continued to decrease over time. After 8 weeks, NRS scores improved by ≥ 30% from baseline in 113 patients (69.3%). Twenty-four patients (12.8%) stopped mirogabalin treatment due to adverse events. Somnolence (26.7%), dizziness (12.3%), edema (5.9%), and weight gain (0.5%) were noted as adverse events of mirogabalin. CONCLUSIONS: The results of this investigation indicate that mirogabalin is safe and effective for reducing peripheral neuropathic pain.

Mirogabalin besylate in the treatment of neuropathic pain.

Neuropathic pain (NeP) is a global cause of suffering and debilitation leading to significant morbidity and reduced quality of life. New treatments are needed to address the growing prevalence of NeP and its impact on sleep, mood and functionality. Mirogabalin besylate (mirogabalin, Tarlige) is a gabapentinoid therapy developed by Daiichi Sankyo which is approved in Japan for the treatment of postherpetic neuralgia and painful diabetic peripheral neuropathy. Mirogabalin has a potent pain-modulating effect with a unique high affinity and prolonged dissociation rate for the a2delta-1 subunit of voltage-gated calcium (Ca2+) channels (VGCCs) on the dorsal root ganglion resulting in more sustained analgesia compared with traditional gabapentinoids. Additionally, mirogabalin has a superior adverse events (AEs) profile due to a rapid dissociation from the a2delta-2 subunit of VGCCs potentially implicated in central nervous system-specific AEs. The most common AEs for mirogabalin are dizziness (approximately 8-16%), somnolence (approximately 6-24%) and headache (approximately 6-14%), with a lower incidence of constipation, nausea, diarrhea, vomiting, edema, fatigue and weight gain. Postmarketing studies are required to evaluate its analgesic durability and efficacy when combined with other antineuropathic agents such as tricyclics, duloxetine and tramadol/tapentadol.

The mirogabalin ALDAY phase 3 program in pain associated with fibromyalgia: the lessons learned.

Aims: The main aim of this work was to identify and to share the lessons learned from the negative outcome of the mirogabalin ALDAY phase 3 clinical program in pain associated with fibromyalgia. These lessons are important to improve planning and design of future phase 3 programs in fibromyalgia.Methods: A systematic review from Cochrane Library, Medline, Embase, clinicaltrials.gov, pharmaceutical companies, and regulatory agencies' websites, was carried out starting from the development of gabapentin, the first α2δ ligand studied for the treatment of neuropathic pain and ending with the mirogabalin program.Results: Based on the outcome of the main fibromyalgia programs, several differences in design, primary endpoint choice, magnitude of placebo response, presence of an active comparator, and size of the entire clinical program were identified. This analysis focused on the negative primary results of the mirogabalin ALDAY program and found several contributing factors. Above all, the magnitude of placebo response and the unprecedented size of the program were identified. The number of study visits and procedures was also high and highly demanding on all subjects involved in ALDAY.Outcome: In terms of main lessons learned from ALDAY, the first was the need for a comprehensive patient-focused strategy to preliminarily identify the challenges of fibromyalgia based on patient perspective and study complexity. Second, there was a need for a harmonized, truly patient-centric, global regulatory guidance accepted by regulatory agencies. Third, ALDAY proved that a phase 2 proof of concept, dose ranging study is necessary before commencing any phase 3 program in fibromyalgia.

Cost-effectiveness of mirogabalin for the treatment of post-herpetic neuralgia in Taiwan.

Objectives: To assess the cost-effectiveness of mirogabalin versus no treatment or pregabalin in patients with post-herpetic neuralgia (PHN) from a third-party perspective in Taiwan.Methods: A Markov model, which was developed with 2-week cycles and 1-year time horizon from the Taiwanese National Health Insurance Administration perspective, consisted of three health states: "mild," "moderate," and "severe" pain. Average daily pain score (ADPS) was assessed at the end of each cycle. Patients either remained in, or transitioned from, their assigned health state to a different state according to their pain score changes. All patients entered the model in "moderate" (4 ≤ ADPS <7) or "severe" (7 ≤ ADPS ≤ 10) pain health states. Efficacy data was informed by the pivotal Phase III trial, or by a network meta-analysis (NMA). Utility values were obtained from published literature and cost data from Taiwanese clinical experts and the Taiwan National Health Insurance Administration, using 2018 New Taiwan dollar (NT$). Probabilistic analysis was conducted to test the robustness of base case results.Results: Head-to-head analysis showed mirogabalin 30 mg to be cost-effective versus placebo in PHN. The deterministic analysis estimated a quality-adjusted life years gain of 0.041 at an ICER of NT$11,231 (US$365) versus no treatment (ICER: NT$274,567 [US$8,900]). In the NMAs, mirogabalin was cost-effective compared to pregabalin 150 mg (ICER: NT$515,881 [US$16,720]) and 300 mg (ICER: NT$201,671 [US$6,535]). Mirogabalin 30 mg dominated pregabalin 600 mg. Results from sensitivity and scenario analyses confirmed these results.Conclusion: Mirogabalin 30 mg, a potent and selective α2δ ligand, is a cost-effective treatment option for PHN in Taiwan, with ICERs below the willingness-to-pay threshold.

PNU-282987 Attenuates Intestinal Epithelial Barrier Dysfunction in LPS-Induced Endotoxemia.

PNU-282987, the α7 acetylcholine receptor(α7nAchR) agonist, has been repeatedly reported to play a key role in anti-inflammatory action of multiple disease. However, little is known about its effect on LPS-induced intestinal epithelial barrier dysfunction. This study investigated the protective effects and mechanisms of PNU-282987 on intestinal epithelial barrier dysfunction in lipopolysaccharide(LPS)-induced endotoxemic rats. Endotoxemia models were induced by intraperitoneal injection of 10 mg/kg LPS. In the endotoxemic group, results showed increases in ileum mucosal permeability, ultrastructural damage of tight junction and redistribution of zonula occludens-1, apoptosis of intestinal epithelial cells and caspase-3 activation. These changes were significantly improved after PNU-282987 administration(P < 0.05). Pretreatment with α-bungarotoxin before PNU-282987 administration reversed the effects of PNU-282987(P < 0.05). These results indicate that PNU-282987 exerts protective effects on intestinal epithelial barrier dysfunction in LPS-induced endotoxemic rats, and its mechanism may involve the improvement of zonula occludens-1 and inhibition of enterocyte apoptosis in an α7nAchR-dependent manner.

Anxiolytic effects of the novel α2δ ligand mirogabalin in a rat model of chronic constriction injury, an experimental model of neuropathic pain.

RATIONALE: Psychiatric disorders such as anxiety and depression are frequently observed in neuropathic pain patients, and negatively impact their quality of life. Mirogabalin is a novel ligand for the α2δ subunit of voltage-gated calcium channels and has unique binding characteristics to α2δ subunits and potent and long-lasting analgesic effects in neuropathic pain models. OBJECTIVES: To provide further information on the pharmacological profile of mirogabalin and its utility for chronic pain therapy, we investigated its anxiolytic effects in an experimental animal model for neuropathic pain. METHODS: In chronic constriction injury (CCI) model rats, mechanical hypersensitivity was determined by the von Frey test. Anxiety- and depression-related behaviours were evaluated using the elevated plus maze test and forced swimming test, respectively. RESULTS: CCI model rats showed sustained tactile allodynia followed by anxiety-related behaviours, not depression-related behaviours. The tactile allodynia (significant decreases in paw withdrawal threshold) developed within 2 weeks after model preparation, whereas the anxiety-related behaviours (significant decreases in the number of entries and time spent in open arms and significant increases in time spent in closed arms) were observed at 5 weeks but not 4 weeks after model preparation. Single oral administration of mirogabalin (3 or 10 mg/kg) dose-dependently alleviated the above-mentioned anxiety-related behaviours and tactile allodynia. CONCLUSIONS: CCI model rats showed anxiety-related behaviours in a time-dependent manner in the elevated plus maze test. Mirogabalin alleviated both the anxiety-related behaviours and tactile allodynia in CCI model rats. Mirogabalin may provide effective anxiety relief as well as pain relief in patients with neuropathic pain.

Long-term safety and efficacy of mirogabalin in Asian patients with diabetic peripheral neuropathic pain.

AIMS/INTRODUCTION: Diabetic peripheral neuropathic pain (DPNP) affects the functionality, mood and sleep patterns of patients with diabetes. Mirogabalin, an α2 δ ligand with a slower dissociation for α2 δ-1 versus α2 δ-2 subunits, showed efficacy and safety in a randomized, double-blind, placebo-controlled, 14-week study in Asian patients with DPNP. This open-label extension study evaluated the long-term safety and efficacy of mirogabalin in Asian patients with DPNP. MATERIAL AND METHODS: This 52-week open-label extension study was carried out in Japan, Korea and Taiwan in patients with DPNP. Patients received mirogabalin, initiated at 5 mg twice daily and increased to a flexible maintenance dosage of 10 or 15 mg twice daily. Adverse events were monitored throughout the study. Patients provided a self-assessment of pain using the Short-Form McGill Pain Questionnaire. RESULTS: Of the 214 patients who entered the study, 172 (80.4%) completed the extension study. Of 172 patients who completed the study, 149 received the highest dosage of mirogabalin (15 mg twice daily). The most common treatment-emergent adverse events were nasopharyngitis, diabetic retinopathy, peripheral edema, somnolence, diarrhea, increased weight and dizziness. Most treatment-emergent adverse events were mild or moderate in severity. The incidence of treatment-emergent adverse events leading to treatment discontinuation was 13.1%. The visual analog scale and all other Short-Form McGill Pain Questionnaire subscales (sensory score, affective score, total score and present pain intensity) generally decreased over time from baseline until week 52. CONCLUSIONS: This extension study showed the safety and efficacy of a long-term flexible dosing regimen of mirogabalin 10 or 15 mg twice daily in patients with DPNP.

Ferula hermonis: A Review of Current Use and Pharmacological Studies of its Sesquiterpene Ester Ferutinin.

Ferula hermonis Boiss, is an endemic plant of Lebanon, locally known as "shilsh Elzallouh". It has been extensively used in the traditional medicine as an aphrodisiac and for the treatment of sexual impotence. Crude extracts and isolated compounds of ferula hermonis contain phytoestrogenic substances having a wide spectrum of in vitro and in vivo pharmacological properties including anti-osteoporosis, anti-inflammatory, anti-microbial and anti-fungal, anti-cancer and as sexual activity enhancer. The aim of this mini-review is to highlight the traditional and novel applications of this plant's extracts and its major sesquiterpene ester, ferutinin. The phytochemical constituents and the pharmacological uses of ferula hermonis crude extract and ferutinin specifically will be discussed.

α7 nicotinic receptor full agonist reverse basolateral amygdala hyperactivity and attenuation of dopaminergic neuron activity in rats exposed to chronic mild stress.

Neuroimaging and preclinical studies showing that nicotinic receptors (nAChR) may play a role in mood control has increased interest in targeting the cholinergic system for treatment of major depressive disorder. Indeed, modulation of nAChRs in the basolateral amygdala (BLA) are sufficient to produce an anti-immobility effect in the mouse tail suspension test. However, how α7 nAChR modulation impacts BLA neuronal activity in vivo as well as the downstream mechanisms involved in its mood-related effects are not understood. In this work, we used the unpredictable chronic mild stress (CMS) model to investigate the mechanisms underlying the antidepressant-like effect of an α7 nAChR full agonist on BLA-induced changes in dopaminergic neurotransmission. Male adult Sprague-Dawley rats were exposed to four weeks of CMS. Behavioral and electrophysiological experiments were performed within one week following stress. CMS exposure increased rats' immobility time in the forced swimming test, decreased the number of spontaneously active dopamine neurons in the ventral tegmental area and increased the firing rate of putative projection neurons in the BLA. Stress-induced behavioral and electrophysiological changes were reversed by a single systemic administration of PNU282987. In summary, our findings corroborate previous descriptions of a potential rapid antidepressant effect for the α7 nAChR full agonist. This effect appears to involve a mechanism distinct from those of classic antidepressants: normalization of BLA hyperactivity and, consequently, of DA hypofunction. These observations corroborate the role of α7 nAChR as a potential target for novel antidepressant drug development.

Effect of α7nAChR on learning and memory dysfunction in a rat model of diffuse axonal injury.

Diffuse axonal injury (DAI) is the predominant effect of severe traumatic brain injury and significantly contributes to cognitive deficits. The mechanisms that underlie these cognitive deficits are often associated with complex molecular alterations. α7nAChR, one of the abundant and widespread nicotinic acetylcholine receptors (nAChRs) in the brain, plays important physiological functions in the central nervous system. However, the relationship between temporospatial alterations in the α7nAChR and DAI-related learning and memory dysfunction are not completely understood. Our study detected temporospatial alterations of α7nAChR in vulnerable areas (hippocampus, internal capsule, corpus callosum and brain stem) of DAI rats and evaluated the development and progression of learning and memory dysfunction via the Morris water maze (MWM). We determined that α7nAChR expression in vulnerable areas was mainly reduced at the recovery of DAI in rats. Moreover, the escape latency of the injured group increased significantly and the percentages of the distance travelled and time spent in the target quadrant were significantly decreased after DAI. Furthermore, α7nAChR expression in the vulnerable area was significantly positively correlated with MWM performance after DAI according to regression analysis. In addition, we determined that a selective α7nAChR agonist significantly improved learning and memory dysfunction. Rats in the α7nAChR agonist group showed better learning and memory performance than those in the antagonist group. These results demonstrate that microstructural injury-induced alterations of α7nAChR in the vulnerable area are significantly correlated with learning and memory dysfunctions after DAI and that augmentation of the α7nAChR level by its agonist contributes to the improvement of learning and memory function.