Télesphore Benoît Nguelefack

Acacia sieberiana (syn. Vachellia sieberiana), widely used in African traditional medicine for pain, was investigated using an ethnopharmacology-guided workflow integrating LC-MS/MS-based metabolomics and molecular networking to prioritize bioactive secondary metabolites. Fractionation of the ethanolic stem bark extract enabled targeted isolation and identification of piperine (1) and moupinamide (3) by HRMS and NMR. Moupinamide and its positional isomer (tamgermanetin) were synthesized via HATU-mediated coupling to support preliminary structure–activity studies. In a capsaicin-induced mouse model, the extract significantly attenuated acute nociceptive behavior without affecting the secondary mechanical hypersensitivity. Functional screening using human iPSC-derived nociceptors in a multielectrode array (MEA) platform showed that moupinamide potently reduced neuronal firing, with reduced efficacy under high-heat conditions, suggesting a non-TRPV1-mediated mechanism. GPCR profiling of moupinamide revealed minimal receptor engagement, and further pharmacological studies demonstrated retained activity under potassium channel blockade and suppression of Nav1.7-induced hyperexcitability, consistent with voltage-gated sodium channel modulation. These findings highlight A. sieberiana-derived alkaloid amides as promising nonopioid analgesic leads and underscore the utility of metabolomics-guided discovery strategies.

Efforts to resolve the opioid crisis are hindered by withdrawal syndrome, whose neurochemical basis across brain regions remains unclear. This study attempted to find the naloxone dose that best induce the behavioral and neurochemical alterations, and the association between the two. Mice were treated with morphine (48 mg/kg/day) for ten days, during which tactile allodynia, grip test, and locomotor activity were monitored. On day 10, morphine treated groups received naloxone intraperitoneally at 3 or 5 mg/kg. Then, withdrawal behavior (jump, grooming, and wed dog shake) was observed. On day 11, animals underwent hot plate and acetone tests. Thereafter, serum, Prefrontal cortex (PFC), striatum, hippocampus, cerebellum, the rest of the brain (RB), and spinal cord (SC) were collected to assay IL-1β, TNF-α, dopamine, noradrenaline and acetylcholine esterase (AChE) activity. Principal component analysis was used to identify relationship between biochemical and behavior. Morphine administration decreased body mass and tactile pain threshold. Naloxone reduced the time on grid and animal mobility. It increased jumps and wet dog shake. A relationship was observed between AChE in the RB and SC, and the locomotor activity. Withdrawal global score was related to norepinephrine level in the PFC, cerebellum and RB. Pain-like behaviour was related to dopamine level in the striatum and the SC. Naloxone 3 mg/kg was the more effective dose to induce withdrawal syndrome. The behavioural signs of dependence and withdrawal syndrome are mediated through a complex intermingled biochemical circuitry that differentially implicate dopamine, norepinephrine and cholinergic tone from SC and distinct brain regions.

Jateorhiza macrantha (Menispermaceae) is used in folk medicine in Africa for gastrointestinal and inflammatory disorders. However, its efficacy against inflammatory pain and associated neuro‐oxidative stress remains uncharacterized. This study evaluated the antihypernociceptive, anti‐inflammatory, and antipyretic properties of J. macrantha aqueous (AEJM) and methanolic (MEJM) leaf extracts in a rat model of complete Freund′s adjuvant (CFA)–induced persistent inflammation. Chronic inflammatory pain was induced in male Wistar rats by intraplantar injection of CFA (50 μ L). The test extracts were administered orally (100–400 mg/kg) for 14 days. Mechanical, cold, and thermal nociception were evaluated using Von Frey filaments, acetone test, and hot‐plate assay, respectively. Paw edema and rectal temperature were monitored to assess anti‐inflammatory and antipyretic effects. Serum levels of TNF‐ α , IL‐1 β , and IL‐6 were quantified, whereas oxidative stress markers (MDA, CAT, SOD, and GSH) were measured in brain and spinal cord tissues. Moreover, qualitative phytochemical profiling was performed. AEJM and MEJM significantly ( p < 0.05– p < 0.001) reduced paw edema and fever, increased paw withdrawal thresholds and thermal latencies. These improvements correlated with a significant downregulation of serum TNF‐ α , IL‐1 β , and IL‐6. Furthermore, both extracts significantly lowered MDA levels and increased antioxidant defenses (SOD, CAT, and GSH) in the brain and spinal cord. Notably, AEJM restored the locomotor performance compared with diclofenac. Phytochemical analysis showed flavonoids, saponins, steroids and tannins. AEJM and MEJM exert noteworthy anti‐inflammatory, antihypernociceptive, and antipyretic effects mediated through the concurrent suppression of proinflammatory cytokines and reinforcement of central antioxidant systems. These scientifically validate its traditional use.

Objectives: Previous studies demonstrated that aqueous and methanolic extracts from the leaves of Pittosporum mannii possess analgesic but not anti-inflammatory activities. The present work attempted to understand the lack of the anti-inflammatory effects of those extracts. Materials and methods: Plant extracts were given orally at the doses of 75, 150 and 300 mg/kg on inflammation induced by Complete Freund’s Adjuvant (CFA; 100 µL; i.pl.). Equally the acetic acid (0.7%) induced vascular permeability and leukocytes mobilizations were investigated. Extracts (75, 150 and 300 mg/kg) were given orally one hour before inflammation induction. The effects of extracts were also evaluated on stimulated and non-stimulated macrophages at the concentration of 10, 30, 100 and 300 µg/mL for 8 and 24 h.. Results: Aqueous and methanolic extracts administration have no effects on CFA induced inflammation model. However, both extracts significantly (p<0.05, p<0.01 and p<0.001) increased capillary permeability accentuation induced by acetic acid in rat at dose 75, 150, 300 mg/kg. Both extracts significantly (p<0.05, p<0.01 and p<0.001) inhibited leukocytes, granulocytes and lymphocytes migration in the rat’s peritoneal fluid with high effect for AEPM at the dose of 75 mg/kg. Animals mean platelet volume and in vitro hemolysis of erythrocytes induced by heat were not significantly inhibited by extracts. For the NO production by non-stimulated macrophages and stimulated (using LPS), no significant difference was observed. Conclusion: These results suggest that, aqueous and methanolic extracts from the leaves of Pittosporum mannii present no anti-inflammatory activities despite their ability to inhibit leukocytes migration.

Type 2 diabetes, mainly driven by insulin resistance (IR), represents 90% of diabetic cases and has been related to bone fragility and fractures. However, it is unclear how hyperglycaemia, IR and oxidative stress interplay to induce bone fragility. This study was then undertaken to examine the contribution and the interconnection of hyperglycaemia, insulinopenia, IR and oxidative stress to bone fragility, as well as the time‐ and severity‐dependent effects of insulin impairment on bone fragility and its reversibility. IR was induced by dexamethasone in three different protocols: 1 mg/kg/day/im for 7 consecutive days; 500 μ g/kg/day/im for 7 consecutive days, the dose was changed to 100 μ g/kg/day/im for the following 14 days; and 200 μ g/kg/day/im for 21 consecutive days. Fasting glycaemia, glucose tolerance test (GTT) and insulin tolerance test (ITT) were performed at the end of each treatment period while body mass was recorded daily. A control group receiving DMSO 4% was constituted for each protocol. Following euthanasia, the serum was collected for lipid profile, calcium, phosphate and alkaline phosphatase. The pancreas and liver were collected for the assessment of oxidative stress markers. Tibia and femur were collected to assess calcium phosphate and histological modifications. Dexamethasone induced an increase in baseline blood glucose and insulin intolerance while promoting glucose tolerance. A decrease in animal body weight as well as disturbances in oxidative stress, calcium and lipid profiles were observed in dexamethasone‐treated animals. Bone histopathology showed loss of bone matrix, decreased collagen and an increase in Trap expression in dexamethasone‐treated rats. Bone alterations were positively correlated with oxidative stress and IR. These results show that the phosphocalcic metabolism disruption and bone structure alterations induced by glucocorticoids are related to IR (time and severity) and oxidative stress status. Surprisingly, the relation is more effective on the tibia than the femur.

Rationale and Objective: The pain–depression dyad is highly prevalent and has reciprocal psychological and behavioral effects, leading to poor quality of life, increased disability, and challenging therapeutic outcomes. In an attempt to find better substances that can target pain–depression comorbidity, we examined the effect of aqueous (AE) and ethanol (EE) extracts from Acacia sieberiana ( A. sieberiana ) stem bark on reserpinized mice (female and male Swiss albino mice aged 2‐3 months). Methods: The dyad was induced with 3 injections (Days 1–3) of reserpine (1 mg/kg/day, s.c .). Then, animals were treated (Days 4–8) with plant extracts (25, 50 and 100 mg/kg/day, p.o .) or L‐tryptophane (100 mg/kg/day, i.p .). Pain‐like (tactile and cold allodynia) and depression‐like (pole, tail suspension, and force swimming tests) behavioral parameters were evaluated on Days 4 and 8. On Day 9, animals were sacrificed for the quantification of acetylcholinesterase activity, oxidative stress parameters, total catecholamines, dopamine, serotonin, IL‐1β, and TNF‐α levels in the brain or spinal cord. IL‐1β and TNF‐α were also assayed in the serum. The acute toxicity and phytochemical analysis of EE were conducted. Results: Reserpine‐induced tactile and cold allodynia, depression‐like behavior, increased serum IL‐1β and TNF‐α, brain acetylcholinesterase activity, and decreased catecholamine concentration were all reversed by AE and EE. Plant extracts significantly increased dopamine levels and reduced oxidative stress in the brain and/or spinal cord. No significant effect was observed on brain serotonin and TNF‐α. EE elicited the best pharmacological activity and was nontoxic. LC–MS/MS molecular networking phytochemical analysis identified 5 compounds with high certainty including piperine, aurantiamide acetate, and asperphenamate. Conclusion: AE and EE are effective against pain and depression. Their pharmacological activities might be related to the modulation of inflammation, oxidative stress and catecholamine, and the presence of bioactive natural products.