Cilostazol pretreatment prevents PTSD-related anxiety behavior through reduction of hippocampal neuroinflammation.

Current pharmacological treatments against post-traumatic stress disorder (PTSD) lack adequate efficacy. As a result, intense research has focused on identifying other molecular pathways mediating the pathogenesis of this condition. One such pathway is neuroinflammation, which has demonstrated a role in PTSD pathogenesis by causing synaptic dysfunction, neuronal death, and functional impairment in the hippocampus. Phosphodiesterase (PDE) inhibitors (PDEIs) have emerged as promising therapeutic agents against neuroinflammation in other neurological conditions. Furthermore, PDEIs have shown some promise in animal models of PTSD. However, the current model of PTSD pathogenesis, which is based on dysregulated fear learning, implies that PDE inhibition in neurons should enhance the acquisition of fear memory from the traumatic event. As a result, we hypothesized that PDEIs may improve PTSD symptoms through inhibiting neuroinflammation rather than long-term potentiation-related mechanisms. To this end, we tested the therapeutic efficacy of cilostazol, a selective inhibitor of PDE3, on PTSD-related anxiety symptoms in the underwater trauma model of PTSD. PDE3 is expressed much more richly in microglia and astrocytes compared to neurons in the murine brain. Furthermore, we used hippocampal indolamine 2,3-dioxygenase 1 (IDO) expression and interleukin 1 beta (IL-1ß) concentration as indicators of neuroinflammation. We observed that cilostazol pretreatment prevented the development of anxiety symptoms and the increase in hippocampal IDO and IL-1ß following PTSD induction. As a result, PDE3 inhibition ameliorated the neuroinflammatory processes involved in the development of PTSD symptoms. Therefore, cilostazol and other PDEIs may be promising candidates for further investigation as pharmacological therapies against PTSD.

Phosphodiesterase inhibitors in psychiatric disorders.

RATIONALE: Challenges in drug development for psychiatric disorders have left much room for the introduction of novel treatments with better therapeutic efficacies and indices. As a result, intense research has focused on identifying new targets for developing such pharmacotherapies. One of these targets may be the phosphodiesterase (PDE) class of enzymes, which play important roles in intracellular signaling. Due to their critical roles in cellular pathways, these enzymes affect diverse neurobiological functions from learning and memory formation to neuroinflammation. OBJECTIVES: In this paper, we reviewed studies on the use of PDE inhibitors (PDEIs) in preclinical models and clinical trials of psychiatric disorders including depression, anxiety, schizophrenia, post-traumatic stress disorder (PTSD), bipolar disorder (BP), sexual dysfunction, and feeding disorders. RESULTS: PDEIs are able to improve symptoms of psychiatric disorders in preclinical models through activating the cAMP-PKA-CREB and cGMP-PKG pathways, attenuating neuroinflammation and oxidative stress, and stimulating neural plasticity. The most promising therapeutic candidates to emerge from these preclinical studies are PDE2 and PDE4 inhibitors for depression and anxiety and PDE1 and PDE10 inhibitors for schizophrenia. Furthermore, PDE3 and 4 inhibitors have shown promising results in clinical trials in patients with depression and schizophrenia. CONCLUSIONS: Larger and better designed clinical studies of PDEIs in schizophrenia, depression, and anxiety are warranted to facilitate their translation into the clinic. Regarding the other conditions discussed in this review (most notably PTSD and BP), better characterization of the effects of PDEIs in preclinical models is required before clinical studies.

Neuronal nitric oxide synthase inhibition accelerated the removal of fluoxetine's anxiogenic activity in an animal model of PTSD.

While SSRIs are the current first-line pharmacotherapies against post-traumatic stress disorder (PTSD), they suffer from delayed onset of efficacy and low remission rates. One solution is to combine SSRIs with other treatments. Neuronal nitric oxide synthase (nNOS) has been shown to play a role in serotonergic signaling, and there is evidence of synergism between nNOS modulation and SSRIs in models of other psychiatric conditions. Therefore, in this study, we combined subchronic fluoxetine (Flx) with 7-nitroindazole (NI), a selective nNOS inhibitor, and evaluated their efficacy against anxiety-related behavior in an animal model of PTSD. We used the underwater trauma model to induce PTSD in rats. Animals underwent the open field (OFT) and elevated plus maze tests on days 14 (baseline) and 21 (post-treatment) after PTSD induction to assess anxiety-related behaviors. Between the two tests, the rats received daily intraperitoneal injections of 10 mg/kg Flx or saline, and were injected intraperitoneally before the second test with either 15 mg/kg NI or saline. The change in behaviors between the two tests was compared between treatment groups. Individual treatment with both Flx and NI had anxiogenic effects in the OFT. These effects were associated with modest increases in cFOS expression in the hippocampus. Combination therapy with Flx + NI did not show any anxiogenic effects, while causing even higher expression levels of cFOS. In conclusion, addition of NI treatment to subchronic Flx therapy accelerated the abrogation of Flx's anxiogenic properties. Furthermore, hippocampal activity, as evidenced by cFOS expression, was biphasically related to anxiety-related behavior.

Comparison of Side Effects of COVID-19 Vaccines: Sinopharm, AstraZeneca, Sputnik V, and Covaxin in Women in Terms of Menstruation Disturbances, Hirsutism, and Metrorrhagia: A Descriptive-Analytical Cross-Sectional Study.

BACKGROUND: Present study assessed whether Sinopharm, AstraZeneca, Sputnik V, and Covaxin's vaccinated women
reveal a distinct incidence of menstruation disturbances, hirsutism, and metrorrhagia.
Materials and Methods: Data collection was performed from June to August 2021, and 427 women working in seven
selected hospitals in Tehran were studied in this descriptive-analytical cross-sectional study. All of these women had
received one or both doses of the vaccines with one of the assessed vaccines. Required data was collected via questionnaire
and imported to SPSS 16 for further assessment and analysis. Fisher's Exact Test and Chi-Squared test were
main statistical tests used to understand whether any significant relation exists or not.
Results: The participant's mean age and body mass index (BMI) were 29.78 ± 10.55 and 23.27 ± 3.82, respectively.
Three hundred ninety-five cases (92.4%) had received both doses of the vaccines. Also, 154 cases (36.1%) had a history
of COVID-19. A total of 38 cases (8.8%) of menstruation disturbances, 20 cases (4.6%) of metrorrhagia, and 7
cases (1.6%) of hirsutism were reported after receiving the vaccines. There was a significant difference among the
vaccinated groups with the vaccines as mentioned earlier in terms of menstruation disturbances (hypermenorrhea,
dysmenorrhea, Amenorrhea) (P=0.01). The highest and the lowest incidence of menstruation disturbances were recorded
in the group vaccinated with Covaxin (17.6%) and Sputnik V (5%), respectively. There was also no significant
difference amongst the vaccinated groups with the four vaccines regarding the incidence of metrorrhagia and
hirsutism (P=0.10 and P=0.12, respectively). There was no significant relationship between all three complications
incidence with the previous infection concerning all vaccines (coefficient=0.46, 1.27, -0.15 respectively for menstruation
disturbances, metrorrhagia, and, hirsutism).
Conclusion: Seemingly, Covaxin revealed the most side effects in terms of menstruation disturbances. As a result, professionals
must carry out several studies with reasonable samples to recommend the vaccine to those women confidently.

Targeting neuronal nitric oxide synthase and the nitrergic system in post-traumatic stress disorder.

RATIONALE: Current pharmacological approaches to treatment of post-traumatic stress disorder (PTSD) lack adequate effectiveness. As a result, identifying new molecular targets for drug development is necessary. Furthermore, fear learning and memory in PTSD can undergo different phases, such as fear acquisition, consolidation, and extinction. Each phase may involve different cellular pathways and brain regions. As a result, effective management of PTSD requires mindfulness of the timing of drug administration. One of the molecular targets currently under intense investigation is the N-methyl-D-aspartate (NMDA)-type glutamate receptor (NMDAR). However, despite the therapeutic efficacy of drugs targeting NMDAR, their translation into clinical use has been challenging due to their various side effects. One possible solution to this problem is to target signaling proteins downstream to NMDAR to improve targeting specificity. One of these proteins is the neuronal nitric oxide synthase (nNOS), which is activated following calcium influx through the NMDAR. OBJECTIVE: In this paper, we review the literature on the pharmacological modulation of nNOS in animal models of PTSD to evaluate its therapeutic potential. Furthermore, we attempt to decipher the inconsistencies observed between the findings of these studies based on the specific phase of fear learning which they had targeted. RESULTS: Inhibition of nNOS may inhibit fear acquisition and recall, while not having a significant effect on fear consolidation and extinction. However, it may improve extinction consolidation or reconsolidation blockade. CONCLUSIONS: Modulation of nNOS has therapeutic potential against PTSD and warrants further development for use in the clinical setting.

Involvement of Cannabinoid Type 2 Receptors in the Favorable Effects of Sumatriptan on the Random-Pattern Skin Flap Survival in Rats: A Novel Potential Target.

INTRODUCTION: Recent investigations have indicated the potential therapeutic role of cannabinoid type 2 (CB2) receptors in various inflammatory-related disorders. However, the role of these receptors has not been studied in skin flap models to date. In this study, we aimed to evaluate the possible involvement of CB2 receptors in the anti-inflammatory effects of sumatriptan, improving the random-pattern skin flap survival in rats. METHODS: In a controlled experimental study, 36 male Wistar rats were randomly divided into 6 study groups (n = 6 per group). Two doses of sumatriptan (0.1 and 0.3 mg/kg) were administered intraperitoneally 30 min before harvesting the flap tissue. In a separate group, SR144528 (a selective CB2 receptor inverse agonist) was injected before the most effective dose of sumatriptan to determine the possible involvement of CB2 receptors in its action. Histopathological examinations, the expression level of CB2 receptors (Western blot analysis), and IL-1ß and TNF-α concentrations (ELISA) were explored in the skin flap sampled tissues. RESULTS: Sumatriptan 0.3 mg/kg remarkably enhanced the skin flap survival in all macroscopic and microscopic investigations compared to the control group (p < 0.001). IL-1ß and TNF-α levels were significantly attenuated (p < 0.001), and the expression of CB2 receptors in skin cells was amplified in rats treated with sumatriptan 0.3 mg/kg (p < 0.05) compared to the control group. However, the administration of SR144528 (2 mg/kg) nullified all the protective effects of sumatriptan 0.3 mg/kg. CONCLUSION: We discovered that CB2 receptors play a crucial role in the favorable effects of sumatriptan on skin flap survival as a novel mechanism of action. So, targeting these receptors seems to be a dependable method in skin flap surgeries to ensure its survival and prevent tissue necrosis. Further experimental and clinical investigations are needed to ensure the safe clinical application of this method.

Sniffer dogs as a screening/diagnostic tool for COVID-19: a proof of concept study.

BACKGROUND: Sniffer dogs are able to detect certain chemical particles and are suggest to be capable of helping diagnose some medical conditions and complications, such as colorectal cancer, melanoma, bladder cancer, and even critical states such as hypoglycemia in diabetic patients. With the global spread of COVID-19 throughout the world and the need to have a real-time screening of the population, especially in crowded places, this study aimed to investigate the applicability of sniffer dogs to carry out such a task. METHODS: Firstly, three male and female dogs from German shepherd (Saray), German black (Kuzhi) and Labrador (Marco) breeds had been intensively trained throughout the classical conditioning method for 7 weeks. They were introduced to human specimens obtained from the throat and pharyngeal secretions of participants who were already reported positive or negative for SARS-COV-2 infection be RT-PCR. Each dog underwent the conditioning process for almost 1000 times. In the meantime another similar condition process was conducted on clothes and masks of COVID-19 patient using another three male and female dogs from Labrador (Lexi), Border gypsy (Sami), and Golden retriever (Zhico) breeds. In verification test for the first three dogs, 80 pharyngeal secretion samples consisting of 26 positive and 54 negative samples from different medical centers who underwent RT-PCR test were in a single-blind method. In the second verification test for the other three dogs, masks and clothes of 50 RT-PCR positive and 70 RT-PCR negative cases from different medical center were used. RESULTS: In verification test using pharyngeal secretion, the sniffer dogs' detection capability was associated with a 65% of sensitivity and 89% of specificity and they amanged to identify 17 out of the 26 positive and 48 out of the 54 true negative samples. In the next verification test using patients' face masks and clothes, 43 out of the 50 positive samples were correctly identified by the dogs. Moreover, out of the 70 negative samples, 65 samples were correctly found to be negative. The sensitivity of this test was as high as 86% and its specificity was 92.9%. In addition, the positive and negative predictive values were 89.6 and 90.3%, respectively. CONCLUSION: Dogs are capable of being trained to identify COVID-19 cases by sniffing their odour, so they can be used as a reliable tool in limited screening.

Role of vitamin A in preventing renal scarring after acute pyelonephritis.

INTRODUCTION: The role of vitamin A in re-epithelialization of the damaged mucosal surfaces has been documented. The aim of this study was to evaluate the role of vitamin A in preventing renal scaring after acute pyelonephritis in children. MATERIALS AND METHODS: This clinical trial study was conducted in children with acute pyelonephritis in Mofid Children Hospital (Tehran, Iran). Patients were randomly divided into two groups to receive ceftriaxone and vitamin A or ceftriaxone only. Dimercaptosuccinic acid (DMSA) renal scintigraphy was performed before the start of the treatment and 6 months later. Results were compared for renal scaring between the two groups. RESULTS: Seventy-six patients (11 boys and 65 girls) were enrolled. The mean age was 25 ± 24 months and 54 patients (71.1%) were under 2 years old. The average vitamin A level was 71 ± 24 microg/dL in the treatment group and it was 62 ± 18 µg/dL in the control group. Baseline DMSA scans were comparable between the two groups in terms of scarring (P = .53), but the second DMSA scans showed a significant change in progression of the renal injury and scaring in the control group compared to those treated with vitamin A as well as antibiotic (P < .001). CONCLUSIONS: We found administration of the vitamin A was useful in decreasing the amount of the injury and scarring following the pyelonephritis. Based on our study, vitamin A can be used in conjunction with other treatments in the management of acute pyelonephritis in children.