2-Arylpropionic Acid Pyrazolamides as Cannabinoid CB2 Receptor Inverse Agonists Endowed with Anti-Inflammatory Properties.

Among the most recent proposals regarding the mechanism of action of dipyrone, the modulation of cannabinoid receptors CB1 and CB2 appears to be a promising hypothesis. In this context, the present work describes a series of five novel pyrazolamides (7-11) designed as molecular hybrids of dipyrone metabolites and NSAIDs, such as ibuprofen and flurbiprofen. Target compounds were obtained in good overall yields (50-80%) by classical amide coupling between 4-aminoantipyrine and arylacetic or arylpropionic acids, followed in some cases by N-methylation of the amide group. The compounds presented good physicochemical properties in addition to stability to chemical (pH 2 and 7.4) and enzymatic (plasma esterases) hydrolysis and showed medium to high gastrointestinal and BBB permeabilities in the PAMPA assay. When subjected to functional testing on CB1- or CB2-transfected cells, compounds demonstrated an inverse agonist profile on CB2 receptors and the further characterization of compound LASSBio-2265 (11) revealed moderate binding affinity to CB2 receptor (Ki = 16 µM) with an EC50 = 0.36 µM (Emax = 63%). LASSBio-2265 (11) (at 1, 3, and 10 mg/kg p.o.) was investigated in the formalin test in mice and a remarkable analgesic activity in the late inflammatory phase was observed, suggesting it could be promising for the treatment of pain syndromes associated with chronic inflammatory diseases.

Glaucoma Workup in Congenital Zika Syndrome.

PURPOSE: The main aim of this study was to perform a glaucoma workup in infants with congenital Zika syndrome (CZS). PATIENT AND METHODS: This cross-sectional study included 188 eyes of 107 children (1.1±0.3 y; range, 0.3 to 1.8 y) with CZS. The confirmation of the syndrome was possible in 77 of 107 (72.0%) of the enrolled infants based on positive immunoglobulin M antibody capture enzyme-linked immunosorbent assay for Zika virus in the cerebrospinal fluid. All infants underwent a complete ophthalmic examination and bilateral fundus imaging was captured using a wide-angle digital fundus camera (RetCam). RESULTS: Five eyes (2.6%) presented 2 criteria for glaucoma diagnosis: 1 eye (0.5%) presented increased intraocular pressure and increased vertical cup-to-disc ratio (CDR); 3 eyes (1.6%) presented increased horizontal corneal diameter and increased vertical, and 1 eye (0.5%) presented myopia related to increased axial length and increased vertical CDR. When excluding the CDR criterion, there was no case of glaucoma in this sample. A significant correlation was observed between high vertical CDR and small cephalic perimeter at birth (P=0.002) and the presence of clinical macular lesions (P=0.031). CONCLUSION AND RELEVANCE: Although childhood glaucoma was not detected in this sample, increased vertical CDR is present in children with CZS, associated with microcephaly and clinical macular lesions at birth. This finding may lead to a misdiagnosis of glaucoma.

Evaluation of ß-Aminocarboxylic Acid Derivatives in Hippocampal Excitatory Synaptic Transmission.

ß-Aminocarboxylic acid derivatives (LINS04 series) were screened with the aim to explore their potential functional role in excitatory synaptic transmission in the central nervous system. We used field recordings in rat hippocampal slices to investigate the effects of the LINS04 series on the synaptic transmission at hippocampal CA1 synapses. We found that LINS04008 and LINS04009 increase the size of the evoked field excitatory postsynaptic potential (EPSP) in a dose-dependent manner. The concentration-response curve shows that the efficacy of LINS04008 is highest in the series (EC50 = 91.32 µM; maximum fEPSP 44.97%). The esters LINS04006 and LINS04005 did not affect the synaptic evoked activity. These data provide the first evidence of synaptic activity enhancement by these compounds and the importance of the acidic group to the activity. This set of data may provide direction for a strategic procedure to restore the glutamate synaptic transmission; however, further studies are needed to establish a more complete picture of how these molecules act on the glutamate transmission, which are in our mind for the next steps.

Effects of a Flavonoid-Rich Fraction on the Acquisition and Extinction of Fear Memory: Pharmacological and Molecular Approaches.

The effects of flavonoids have been correlated with their ability to modulate the glutamatergic, serotoninergic, and GABAergic neurotransmission; the major targets of these substances are N-methyl-D-aspartic acid receptor (NMDARs), serotonin type1A receptor (5-HT1ARs), and the gamma-aminobutyric acid type A receptors (GABAARs). Several studies showed that these receptors are involved in the acquisition and extinction of fear memory. This study assessed the effects of treatment prior to conditioning with a flavonoid-rich fraction from the stem bark of Erythrina falcata (FfB) on the acquisition and extinction of the conditioned suppression following pharmacological manipulations and on gene expression in the dorsal hippocampus (DH). Adult male Wistar rats were treated before conditioned fear with FfB, vehicle, an agonist or antagonist of the 5-HT1AR, GABAARs or the GluN2B-NMDAR or one of these antagonists before FfB treatment. The effects of these treatments on fear memory retrieval, extinction training and extinction retrieval were evaluated at 48, 72, and 98 h after conditioning, respectively. We found that activation of GABAARs and inactivation of GluN2B-NMDARs play important roles in the acquisition of lick response suppression. FfB reversed the effect of blocking GluN2B-NMDARs on the conditioned fear and induced the spontaneous recovery. Blocking the 5-HT1AR and the GluN2B-NMDAR before FfB treatment seemed to be associated with weakening of the spontaneous recovery. Expression of analysis of DH samples via qPCR showed that FfB treatment resulted in the overexpression of Htr1a, Grin2a, Gabra5, and Erk2 after the retention test and of Htr1a and Erk2 after the extinction retention test. Moreover, blocking the 5-HT1ARs and the GluN2B-NMDARs before FfB treatment resulted in reduced Htr1a and Grin2b expression after the retention test, but played a distinct role in Grin2a and Erk2 expression, according session evaluated. We show for the first time that the serotoninergic and glutamatergic receptors are important targets for the effect of FfB on the conditioned fear and spontaneous recovery, in which the ERK signaling pathway appears to be modulated. Further, these results provide important information regarding the role of the DH in conditioned suppression. Taken together, our data suggest that FfB represents a potential therapy for preventing or treating memory impairments.

Which patients with headache do not seek medical attention?

OBJECTIVES: To evaluate why patients do not discuss their headaches with their doctors and to compare these patients with those who seek medical assistance for headache. METHOD: Cross-sectional study. A total of 200 consecutive patients attended by family doctors had their complaints registered. Those with headaches were interviewed. A semi-structured questionnaire, Headache Impact Test and Hospital Anxiety and Depression Scale were used. RESULTS: Fifty-two percent had headaches. Ten percent sought medical assistance for headache, 11% already had received some form of medical assistance for headache. There was no association between headache disability and seeking a doctor for headache. Patients that did not seek a doctor for headache had a higher prevalence of tension-type headache (59.6% vs. 22.1%; P < .01), a lower prevalence of migraine with aura (32.3% vs. 40.5%; P < .01), headache intensity (5.4 vs. 6.8; P = .01) and frequency (4.2 × 7.4 days/month; P < .01). Fifty-two percent of them needed preventive treatment. Most of them did not seek a doctor because their headaches were mild or received relief from painkillers. CONCLUSIONS: Patients who did not seek medical assistance for headache had more tension-type headache, less migraine with aura, lower headache intensity and frequency, but the same headache disability. Most of them needed preventive treatment and did not seek doctors because their headache was mild or received relief from painkillers.

Neuromodulatory property of standardized extract Ginkgo biloba L. (EGb 761) on memory: behavioral and molecular evidence.

Although it has been suggested that the standardized Ginkgo biloba leaf extract (Egb 761) may have a beneficial effect on memory, the cellular and molecular changes that underlie this process are not yet well defined. The present study evaluated the effects of acute (one dose) or subacute treatments (one daily dose/seven days) with EGb 761 (0.5 g kg(-1) and 1.0 g kg(-1)) on rats submitted to a conditioned emotional response (CER) in comparison with positive (4 mg kg(-1) Diazepam) and negative (12%Tween 80) control groups. To this end, eighty (n=10/group) adult, male, Wistar rats (+/-250-300 g) were used in an off-baseline CER procedure. We here observed that the rats submitted to an acute and subacute EGb 761 treatments had acquisition of fear conditioning. Additionally, we investigate if the expression of genes previously associated with classical conditioning (CREB-1 and GAP-43) and new candidate genes (GFAP) are modulated following EGb 761 acute treatment. CREB-1, GAP-43 and GFAP mRNA and protein expressions were evaluated using both quantitative PCR (qPCR) and immunohistochemical analysis, respectively. We here show, for the first time, that EGb 761 modulated GAP-43, CREB-1 and GFAP expression in the prefrontal cortex, amygdala and hippocampus. We observed an underexpression of GAP-43 in all structures evaluated and over-expression of GFAP in the amygdala and hippocampus following acute G. biloba treatment when compared to control group (Tween; p<0.01). GAP-43 expression was decreased in prefrontal cortex and hippocampus in the subacute treatment with EGb 761. Subacute treatment with EGb 761 lead to a decreased CREB-1 in mPFC (p<0.001) and increased in the hippocampus to 1.0 g kg(-1)G. biloba group (p<0.001). The results obtained from immunohistochemical analysis support our aforementioned findings and revealed that the changes in expression occurred within specific regions in the areas evaluated. All together, our findings not only provide new evidence for a role of EGb 761 on memory but also identify molecular changes that underlie the fear memory consolidation.