Michał Szulc

Concurrent use of Withania somnifera (WS, ashwagandha) preparations and ethanol (EtOH) is increasingly common, yet the consequences for glutamatergic signaling remain uncharacterized. Because N-methyl-D-aspartate (NMDA) receptors are a principal target of acute EtOH, we examined whether three purified withanolides modify this response. Zebrafish (Danio rerio) were exposed to withanolide A (WITA), withanone (WIN) or withaferin A (WTFA) at 3–5 days post-fertilization (dpf) and to EtOH (0–4.0% v/v) for 1 h at 5 dpf. Photokinetic behavior was quantified with a normalized dark–light contrast index (DLCI; withanolides at 0–500 µg/L) and grin2aa, grin2bb, grin3a and grin3ba transcripts were measured by RT-qPCR (withanolides at 100 µg/L). EtOH caused a concentration-dependent reduction in DLCI, and photokinetic differentiation was markedly impaired at 2.0% and 4.0%. EtOH increased grin2aa and grin2bb expression and decreased grin3a and grin3ba expression, with grin2bb responding at lower concentrations than grin2aa. The three withanolides produced distinct modulatory profiles. WITA partially preserved photokinetic differentiation at high EtOH concentration and attenuated selected transcriptional responses, whereas WIN showed limited effects. WTFA produced the strongest EtOH-dependent changes in NMDA receptor subunit expression but did not prevent behavioral impairment. These findings indicate compound-specific modulation of acute EtOH-induced behavioral responses and NMDA receptor subunit transcription.

Background: Low-THC Cannabis sativa L. extracts are commonly believed to offer potential alternatives to non-steroidal anti-inflammatory drugs (NSAIDs) for inflammatory pain management. This study evaluated the anti-inflammatory effects of two C. sativa extracts (Tygra, Dora) and pure cannabidiol (CBD) compared with acetylsalicylic acid (ASA) in a carrageenan-induced rat paw inflammation model. Materials and Methods: Fifty male Wistar rats were randomized into five groups: control, ASA (200 mg/kg), CBD (20 mg/kg), Extract B (Tygra), and Extract D (Dora). Treatments were administered intragastrically 30 min after carrageenan injection. Paw volume was measured at 0, 1, 3, 6, and 10 h, and mRNA levels of COX-1, COX-2, TNFα, NFκB, CB1, and CB2 were quantified by qPCR. Results: Unlike ASA, which reduced paw edema and NFκB expression at 10 h, CBD and both extracts increased edema compared to control. Specifically, Extract D induced greater edema than ASA, upregulated CB1 and CB2 (surpassing ASA CB2 levels), decreased TNFα, and reduced right-paw COX-2. Extract B increased edema (3 h vs. ASA), increased TNFα, and showed a positive COX-2/paw volume correlation. Furthermore, paw volume correlated negatively with CB2 under CBD treatment (which also lowered right-paw COX-2) and positively with COX-1 under ASA treatment. Conclusions: The results indicate that ASA has a clear anti-inflammatory effect, whereas CBD and the hemp extracts fail to inhibit—and may even exacerbate—the inflammatory response. Differences in endocannabinoid and inflammatory gene expression suggest extract composition–dependent modulation mechanisms.

Concurrent consumption of ethanol (EtOH) and herbal preparations containing Withania somnifera (WS, ashwagandha) is increasingly common, but the neurobehavioral and molecular consequences of such interactions remain poorly characterized. This study investigated how three purified withanolides—withanolide A (WITA), withanone (WIN), and withaferin A (WTFA)—modulate the effects of acute EtOH exposure in zebrafish (Danio rerio) larvae. Locomotor behavior was quantified under EtOH concentrations ranging from 0 to 4.0%, and the expression of four GABAA receptor subunit genes (gabra1, gabra2, gabrd, gabrg2) was analyzed by qPCR. EtOH alone induced a biphasic locomotor response, with stimulation at low-to-moderate doses and suppression at higher doses. WITA and WIN modulated this pattern in a dose-dependent manner, preserving or enhancing hyperactivity, while WTFA consistently potentiated locomotor suppression. mRNA profile analysis revealed subunit-specific changes, including downregulation of gabra1 and gabra2, compound-dependent regulation of gabrd, and complex gabrg2 responses. These results demonstrate that individual withanolides distinctly shape behavioral and molecular outcomes of EtOH exposure, suggesting specific interactions at the level of inhibitory neurotransmission. The findings provide mechanistic insight into the combined effects of WS-derived compounds and EtOH and highlight the importance of considering such interactions in both experimental and applied contexts.

Inflammation is the critical component of neuropathic pain; therefore, this study aimed to assess the potential anti-inflammatory effects of Cannabis sativa L. extracts in a vincristine-induced model of neuropathic pain. The effects of different doses (5.0–40.0 mg/kg) of two Cannabis sativa L. extracts (B and D) on COX-1, COX-2, TNF-α, and NF-κB mRNA and protein levels were examined in the rat hippocampus, cerebral cortex, and blood lymphocytes. There were statistically significant differences in COX-1, COX-2, and TNF-α mRNA and protein expression in the hippocampus and cerebral cortex, with significant differences in COX-2 and TNF-α in the lymphocytes. Extract D dose-dependently increased COX-1 mRNA and protein in the hippocampus and cortex. In contrast, Extract B dose-dependently increased COX-1 mRNA and decreased COX-2 mRNA (in a dose of 7.5 mg/kg) and TNF-α protein levels in the cortex. Cannabis sativa L. extracts significantly influenced the expression of inflammatory genes and proteins, with effects varying based on dose and tissue type. The increased expression of COX-1, COX-2, and TNF-α (in comparison to groups receiving NaCl, vincristine, and gabapentin) in the rat hippocampus and COX-1 in the cerebral cortex suggests that Cannabis may have a pro-inflammatory effect. Due to species specificity, the results of our research based on rats require confirmation in humans. However, Cannabis sativa should be recommended with caution for treating pain with an inflammatory component.

Przedmiot badań: Migrena jest częstym schorzeniem neurologicznym, stanowiącym istotne wyzwanie terapeutyczne. Pomimo dostępności wielu opcji leczenia, skuteczna profilaktyka pozostaje problemem dla znacznej grupy pacjentów. Cel badań: Celem pracy było przedstawienie głównych grup leków stosowanych w profilaktyce migreny, ze szczególnym uwzględnieniem ich skuteczności, tolerancji oraz ograniczeń wynikających z działań niepożądanych i dostępności. Materiały i metody: Przegląd ma charakter narracyjny. Uwzględniono publikacje dostępne do początku 2025 roku, wyszukane w bazach PubMed, Cochrane Library oraz Google Scholar. Analizie poddano przeglądy systematyczne, metaanalizy oraz badania kliniczne oceniające skuteczność i bezpieczeństwo leków stosowanych w profilaktyce migreny, w tym beta-blokerów, leków przeciwpadaczkowych, przeciwdepresyjnych oraz terapii ukierunkowanych na szlak peptydu związanego z genem kalcytoniny (CGRP). Wyniki: Wśród najczęściej rekomendowanych leków w profilaktyce migreny najlepiej udokumentowaną skuteczność wykazują beta-blokery (propranolol, metoprolol), niektóre leki przeciwpadaczkowe (topiramat, walproinian sodu) oraz trójpierścieniowe leki przeciwdepresyjne, takie jak amitryptylina. Choć są one uznawane za standard pierwszego rzutu, ich stosowanie ograniczają działania niepożądane – m.in. senność, zaburzenia koncentracji czy przyrost masy ciała – które nierzadko prowadzą do przerwania terapii. Coraz większe zainteresowanie budzą nowoczesne leki ukierunkowane na szlak CGRP. Zarówno przeciwciała monoklonalne (erenumab, fremanezumab, galcanezumab, eptinezumab), jak i doustni antagoniści receptora CGRP, tzw. gepanty (rimegepant, atogepant), charakteryzują się wysoką skutecznością i bardzo dobrą tolerancją. Wykazano, że u części pacjentów pozwalają one istotnie zmniejszyć liczbę dni z migreną, często skuteczniej niż terapie tradycyjne, przy znacznie lepszej tolerancji. Ich powszechne stosowanie ograniczają jednak nadal wysokie koszty oraz niska dostępność. Wnioski: Leki klasyczne, takie jak propranolol i topiramat, pozostają podstawowymi opcjami profilaktyki migreny. Terapie celowane w CGRP są obiecującą alternatywą u pacjentów nieskutecznie leczonych metodami standardowymi. Wybór leczenia powinien być indywidualizowany z uwzględnieniem skuteczności, bezpieczeństwa i dostępności preparatów.

Introduction: Cannabis sativa L. (CSL) extract has pain-relieving potential due to its cannabinoid content, so the effects of two CSL extracts on alleviating neuropathic pain were investigated in vivo. Methods and groups: Male Wistar rats (n = 130) were divided into groups and received vincristine (0.1 mg/kg) and gabapentin (60 mg/kg) to induce and relieve neuropathic pain or CSL extracts (D and B). The mRNA and protein expression of the cannabinoid receptors type 1 and 2 (CB1R, CB2R) were evaluated in the cerebral cortex, hippocampus, and lymphocytes. Behavioural tests (Tail-Flick and von Frey) were performed on all animals. Results: VK-induced neuropathic pain was accompanied by decreased CB1R protein level and CB2R mRNA expression in the cortex. Gabapentin relieved pain and increased CB1R protein levels in the hippocampus compared to the vincristine group. Hippocampus CB1R protein expression increased with the administration of extract D (10 mg/kg, 40 mg/kg) and extract B (7.5 mg/kg, 10 mg/kg) compared to VK group. In the cerebral cortex CSL decreased CB1R protein expression (10 mg/kg, 20 mg/kg, 40 mg/kg of extract B) and mRNA level (5 mg/kg, 7.5 mg/kg of extract B; 20 mg/kg of extract D) compared to the VK-group.CB2R protein expression increased in the hippocampus after treatment with extract B (7.5 mg/kg) compared to the VK-group. In the cerebral cortex extract B (10 mg/kg, 20 mg/kg) increased CB2R protein expression compared to VK-group. Conclusion: Alterations in cannabinoid receptor expression do not fully account for the observed behavioural changes in rats. Therefore, additional signalling pathways may contribute to the initiation and transmission of neuropathic pain. The Cannabis extracts tested demonstrated antinociceptive effects comparable to gabapentin, highlighting the antinociceptive properties of Cannabis extracts for human use.

Cancer is a leading cause of death worldwide, and the effectiveness of treatment is consistently not at a satisfactory level. This review thoroughly examines the present knowledge and perspectives of honokiol (HON) in cancer therapeutics. The paper synthesizes critical insights into the molecular mechanisms underlying the observed anticancer effects, emphasizing both in vitro and in vivo studies. The effects of HON application, primarily in the common types of cancers, are presented. Because the therapeutic potential of HON may be limited by its physicochemical properties, appropriate delivery systems are sought to overcome this problem. This review discusses the effect of different nanotechnology-based delivery systems on the efficiency of HON. The data presented show that HON exhibits anticancer effects and can be successfully administered to the site of action. Honokiol exerts its anticancer activity through several mechanisms. Moreover, some authors used the combinations of classical anticancer drugs with HON. Such an approach is very interesting and worth further investigation. Understanding HON’s multiple molecular mechanisms would provide valuable insights into how HON might be developed as an effective therapeutic. Therefore, further research is needed to explore its specific applications and optimize its efficacy in diverse cancer types.

The study aimed to explore in vivo the influence of cannabidiol (CBD) on the development of alcohol tolerance in rats. Rats were treated with ethanol (3.0 g/kg, i.p.) and CBD (20 mg/kg, p.o.) for nine successive days, and rectal body temperature, sedation (sleeping time), and blood alcohol concentration (BAC) were measured. In the prefrontal cortex, hippocampus, and striatum, the cannabinoid (CB1R and CB2R) and dopaminergic (DRD1, DRD2, DRD4, DRD5) receptors’ mRNA level changes were analyzed using the quantitative RT-PCR method. CBD inhibited the development of tolerance to the hypothermic and sedative action of alcohol, coupled with BAC elevation. On a molecular level, the most pronounced effects of the CBD + ethanol interaction in the striatum were observed, where CBD reversed the downregulation of CB2R gene transcription caused by ethanol. For CB1R, DRD1, and DRD2 mRNAs, the CBD + ethanol interaction produced opposite effects than for CB2R ones. In turn, for the transcription of genes encoding dopaminergic receptors, the most potent effect of alcohol as CBD occurred in the hippocampus. However, the combined CBD and alcohol administration showed the same effect for each substance administered separately. Since tolerance is considered a prelude to drug addiction, obtained results allow us to emphasize the thesis that CBD can inhibit the development of alcohol dependence in rats.

The aim of the study was to investigate the effect of baicalein or Scutellaria baicalensis root extract interaction with methyldopa in pregnant spontaneously hypertensive rats (SHR) at the pharmacodynamic, molecular, and biochemical levels. The rats, after confirming pregnancy, received baicalein (200 mg/kg/day, p.o.) and extract (1000 mg/kg/day, p.o.), in combination with methyldopa (400 mg/kg/day; p.o.), for 14 consecutive days, 1 h before blood pressure and heart rate measurements. In the heart and placenta from mothers after giving birth to their offspring, mRNA expression of factors related to inflammatory processes (TNF-α, Il-1β, IL-6) and vascular diseases (TGF-β, HIF-1α, VEGF, PlGF) was measured. Levels of markers of oxidative stress (superoxide dismutase and malondialdehyde) in the placenta and indicators of myocardial damage (troponin cTnC and cTnI, creatine kinase, myoglobin, and lactate dehydrogenase) in the heart were also assessed. Baicalein co-administered with methyldopa was associated with reduced blood pressure, especially during the first three days. The interactions were more pronounced for such factors as TGF-β, HIF-1α, VEGF, and PlGF than TNF-α, Il-1β, and IL-6. Combined application of baicalein and extract with methyldopa may be of value in the development of a new antihypertensive medication intended for patients suffering from preeclampsia or pregnancy-induced hypertension.