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- MakaleYayıncıda açık erişim2026Scopus SJRQ2Dual antidepressant-like and antinociceptive effects of Hypericum olympicum extract in mice: preclinical behavioral evidence
Saltan, Nagehan; Üçel, Umut İrfan; Göger, Fatih; Özkay, Ümide Demir; Can, Özgür Devrim
Hypericum Tourn. ex L. species exhibit well-documented neuropsychopharmacological activities, yet the central effects of Hypericum olympicum L. remain unknown. Given the frequent comorbidity of depressive symptoms and pain, this study aimed to characterize, for the first time, the antidepressant-like and antinociceptive profile of H. olympicum in mice. A methanolic extract of the aerial parts (HoE) was prepared, and its major phenolic constituents were identified by LC-MS/MS. At behaviorally active doses, HoE (2.5 and 5 mg/kg, i.p.) did not impair motor coordination in the Rota-rod test, in contrast to diazepam (2 mg/kg, p.o.), indicating the absence of neuromotor confounding effects. In both the tail suspension test (TST) and the modified forced swim test (MFST), HoE significantly reduced immobility, with effects comparable to those of fluoxetine (30 mg/kg, p.o.). In the MFST, increased swimming behavior without changes in climbing suggested a predominantly serotonergic component. HoE also produced marked antinociceptive effects in multiple nociceptive models. It increased response latencies in the hot-plate, tail-immersion, and tail-clip tests, reflecting activity in supraspinal and spinal thermal and mechanical nociceptive processing. In addition, HoE significantly reduced acetic acid-induced writhing, indicating visceral antinociceptive activity. Morphine (10 mg/kg, i.p.) served as the positive control in pain assays. LC-MS/MS analysis indicated the presence of major phenolic constituents, including hyperoside, myricetin derivatives, caffeoylquinic acid derivatives, a luteolin/kaempferol-type glucoside, and a biflavone of the biapigenin/amentoflavone type. These findings suggest that HoE possesses dual antidepressant-like and antinociceptive properties and support its further evaluation for disorders at the affect–pain interface.
- MakaleYalnız künye2026Scopus SJRQ1Subacute ivermectin–induced affective dysregulation: Evidence for hippocampal microglial and astrocytic activation
Eser, Mustafa; Yazıcı, Cevşen; Kandemir, Ümmühan; Üçel, Umut İrfan; Bozkurt, Mehmet Fatih; Demir Özkay, Ümide; Can, Özgür Devrim
Ivermectin (IVR) is a semi-synthetic macrocyclic lactone widely used against nematodes. Under physiological conditions, its central nervous system (CNS) penetration is limited by P-glycoprotein–mediated efflux at the blood–brain barrier (BBB). Nevertheless, supratherapeutic dosing, BBB-compromising pathologies, concomitant P-glycoprotein inhibitors, or MDR1 variants can enhance CNS entry and precipitate neurotoxicity. To evaluate behavioural and neuroinflammatory sequelae of subacute exposure, rats received IVR (1, 5, or 10 mg/kg; i.p.) once daily for 21 days. Animals were assessed for motor function (activity cage, Rota-rod), affective behaviour (elevated plus maze, modified forced swim test), and cognition (Morris water maze). Assay validation employed diazepam (1 and 3 mg/kg; i.p.), desipramine (30 mg/kg; i.p.), and piracetam (200 mg/kg; i.p.), administered according to their respective protocols. IVR did not alter motor performance or spatial learning and memory across doses. However, 5 and 10 mg/kg reduced the percentage of open-arm entries and increased immobility, consistent with anxiety- and depression-like phenotypes, respectively. At 10 mg/kg, hippocampal immunohistochemistry revealed increased Iba1 and GFAP immunoreactivity within CA1, indicating microglial and astrocytic activation. Quantitative counts demonstrated no significant change in CA1 neuronal number across treatment groups, implying that the observed glial activation occurred in the absence of detectable neuronal loss. Collectively, our data indicate that subacute, high-dose IVR provokes affective behavioural alterations coupled to hippocampal neuroinflammation, while sparing gross motor function and measurable cognitive performance under the present conditions. These findings underscore caution when administering IVR at elevated doses or in settings that compromise BBB integrity and warrant further mechanistic and time-resolved investigation.
- MakaleAçık Erişim2026Scopus SJRQ1Cognitive improvement and hippocampal BDNF/GFAP alterations by Schinus molle essential oil in a rat model of scopolamine-induced amnesia
Üçel, Umut İrfan; Kandemi̇r, Ümmühan; Yazici, Cevşen; Bi̇lgi̇n, Öznur; Turan Yücel, Nazlı; Özek, Temel; Demi̇r Özkay, Ümide; İşcan, Gökalp; Can, Özgür Devrim
Ethnopharmacological relevanceSchinus molle L. (Anacardiaceae) has been traditionally used for conditions related to the nervous system and emotional well-being, often through aromatic preparations. However, its cognition-specific effects have not yet been investigated.Aim of the studyTo assess the cognitive effects of the fruit-derived essential oil of Schinus molle L. (SMEO), administered via oral and inhalation routes, in a rat model of scopolamine-induced amnesia.Materials and methodsSMEO was obtained by hydrodistillation and characterised by GC–MS/GC–FID. Amnesic rats received SMEO for 14 days by inhalation (1% or 3%) or oral gavage (100 or 200 mg/kg). Cognition was assessed by Morris water maze (MWM), passive avoidance (PA), and novel object recognition (NOR) tests; locomotion was measured by activity-meter. Hippocampal BDNF and GFAP immunoreactivity were assessed by immunohistochemistry.ResultsSMEO was dominated by α-phellandrene (48.7%). Scopolamine impaired cognition, whereas SMEO attenuated deficits with efficacy comparable to piracetam. Key behavioural and immunohistochemical findings (main omnibus statistical effects) were as follows: In the MWM, treatment and time effects on escape latency were significant (both p < 0.001), and probe performance improved (p < 0.001). PA retention was restored (p < 0.001) and the NOR index improved (p < 0.001), without locomotor changes (all p > 0.05). Scopolamine reduced hippocampal BDNF immunoreactivity in CA1 and DG (p < 0.01) and CA3 (p < 0.001), which was restored by SMEO via both routes. GFAP immunoreactivity was reduced in CA1/CA3/DG (all p < 0.001) and was rescued selectively after inhalation.ConclusionsThese findings provide preclinical evidence consistent with an ethnopharmacological rationale for SMEO and support further translational work to clarify its relevance beyond this experimental paradigm.
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İncele - MakaleAçık Erişim2023Scopus SJRQ3Reboksetin’in diyabetik sıçanlarda bozulmuş davranış parametreleri üzerindeki yararlı etkileri
Özkay, Ümide Demir; Üçel, Umut İrfan; Yücel, Nazlı Turan; Can, Özgür Devrim; Kandemir, Ümmühan
Amaç: Diyabetik hastalarda duygu-durum hastalıklarının ve kognitif bozukluk insidansının genel popülasyona oranla daha yüksek olduğu bilinmektedir. Bu çalışmada, klinikte antidepresan etkinliği için reçete edilen reboksetin’in sıçanlarda diyabet ile indüklenen davranışsal ve bilişsel değişiklikler üzerine etkinliğinin araştırılması amaçlanmıştır.Gereç ve Yöntem: Sıçanlarda deneysel diyabet modeli 50 mg/kg tek doz streptozotosin enjeksiyonu (i.v.) ile oluşturulnuştur. Reboksetin tedavisine diyabetik komplikasyonların oluşması için 4 hafta beklendikten sonra başlanmıştır. Deney hayvanlarının depresyon ve anksiyete düzeyleri sırasıyla modifiye zorlu yüzme ve yükseltilmiş artı şekilli labirent testleri ile araştırılmış; kognitif performansları ise Morris su tankı ve pasif sakınma testleri ie değerlendirilmiştir. Hayvanlarının motor aktiviteleri de aktivite kafesi ve Rota-rod testleri ile incelenmiştir.Sonuç ve Tartışma: Deneyler sonucunda, diyabetik sıçanların depresyon ve anksiyete düzeylerinin yükseldiği ve bilişsel performanslarının zayıfladığı belirlenmiştir. İki hafta süre ile uygulanan reboksetin tedavisi (8 ve 16 mg/kg) diyabetik sıçanların yüksek depresyon ve anksiyete düzeylerini azaltırken, zayıflamış olan bilişsel performanslarını kayda değer ölçüde güçlendirmiştir. Elde edilen bulgular reboksetin’in diyabete bağlı olarak ortaya çıkan davranışsal ve bilişsel bozuklukların tedavisinde terapötik bir potansiyele sahip olabileceğine işaret etmiştir.
- MakaleAçık Erişim2023Scopus SJRQ1Catecholaminergic and Cholinergic Systems Mediate Beneficial Effect of Vortioxetine on Diabetes-Induced Neuropathic Pain
Turan Yücel, Nazlı; Kandemir, Ümmühan; Üçel, Umut İrfan; Demir Özkay, Ümide; Can, Özgür Devrim
The therapeutic potential of vortioxetine on mechanical hyperalgesia/allodynia was investigated in rats with streptozotocin-induced diabetes, and its possible mechanism of action was elucidated in this study. The obtained findings demonstrated that subacute vortioxetine treatment (5 and 10 mg/kg for 2 weeks) increased the reduced paw-withdrawal thresholds of diabetic rats both in the Randall–Selitto and Dynamic plantar tests. Moreover, the falling latencies of animals did not change in the Rota-rod assessments. These results suggest that vortioxetine administration significantly improved diabetes-induced hyperalgesia and allodynia responses in the rats without affecting their motor coordination. The vortioxetine (5 mg/kg)-induced antihyperalgesic and antiallodynic effects were reversed by AMPT, yohimbine, ICI 118,551, sulpiride and atropine pre-treatments, suggesting the involvement of the catecholaminergic system, α2- and β2-adrenoceptors, D2/3 dopaminergic receptors and cholinergic muscarinic receptors in the exhibited pharmacological activity, respectively. Moreover, the data from the immunohistochemical studies indicated that the inhibition of c-Fos overexpression in dorsal horn neurons also mediates the beneficial effect of this drug. Vortioxetine induced no difference in plasma glucose levels in diabetic rats. If clinical studies confirm these findings, the concomitant beneficial effect of vortioxetine on mood disorders and its neutral activity profile on glycemic control may make it an alternative drug for the treatment of neuropathic pain.
AtıfScopus6WoS4OpenAlex6İncele - MakaleAçık Erişim2022Scopus SJRQ4Tofisopam’ın opioiderjik sistem aracılıklı antinosiseptif etkinliği
Özkay, Ümide Demir; Üçel, Umut İrfan; Yücel, Nazlı Turan; Can, Özgür Devrim; Yazıcı, Cevşen
Amaç: Bu çalışmada Tofisopam’ın antinosiseptif etkinlik potansiyelinin araştırılması ve bu etkiye opioiderjik sistemin olası katılımının aydınlatılması amaçlanmıştır. Gereç ve Yöntem: Tofisopam’ın (25 ve 50 mg/kg) antinosiseptif etkinlik potansiyeli sıcak plaka ve asetik asit ile indüklenen kıvranma testleri ile araştırılmış; farelerin motor koordinasyonları üzerindeki olası etkileri ise Rota-rod testi ile değerlendirilmiştir. Sonuç ve Tartışma: Tofisopam 50 mg/kg dozda, farelerin sıcak plaka testlerindeki reaksiyon sürelerini anlamlı ölçüde uzatmış; kıvranma testlerinde ise kıvranma davranışlarının sayılarını azaltmıştır. Bu bulgular Tofisopam’ın santral ve periferik mekanizmalar aracılıklı antinosiseptif aktiviteye sahip olduğuna işaret etmiştir. Tofisopam, uygulandığı dozlarda, farelerin motor aktivitelerinde anlamlı bir değişikliğe neden olmamıştır. Antinosiseptif etkiye opioid reseptörlerin olası katılımını araştırmak amacı ile yapılan nalokson ön- uygulamaları Tofisopam’ın antinosiseptif aktivitesini ortadan kaldırmıştır. Etkiye aracılık eden opioid reseptör alt-tiplerinin aydınlatılması amacıyla naloksonazin (μ-opioid reseptör blokörü), naltrindol (δ-opioid reseptör blokörü) ve nor-binaltorfimin (ҡ-opioid reseptör blokörü) ile mekanistik çalışmalar yapılmıştır. Her üç ajan da Tofisopam’ın antinosiseptif etkisini antagonize etmiştir. Elde edilen bu bulgular Tofisopam’ın 50 mg/kg dozdaki antinosiseptif etkinliğine μ-, δ- ve ҡ-oipiod reseptörlerin aracılık ettiğini ortaya koymuştur.
- MakaleAçık Erişim2020Scopus SJRQ1Antiamnesic effects of tofisopam against scopolamine-induced cognitive impairments in rats
Üçel, Umut İrfan; Can, Özgür Devrim; Demir Özkay, Ümide; Ulupinar, Emel
In this study, we investigated the potential therapeutic effects of tofisopam, a 2,3-benzodiazepine derivative anxiolytic, on cognitive deficits in rats with scopolamine-induced amnesia. Cognitive performance of the rats was investigated by using the Morris water maze and passive avoidance tests. Changes in motor activity were assessed by using the activity cage and Rota-rod tests and then morphological changes in the hippocampus were assessed via immunohistochemical stainings. The results indicated that scopolamine impaired learning and memory parameters in rats. Worsened cognitive performance, neuronal loss, and decreased hippocampal synaptophysin, Ki-67, and glial fibrillary acidic protein density were observed. Tofisopam administration at a dose of 50 mg/kg for seven days improved the impaired cognitive performance, enhanced the attenuated synaptic transmission in the hippocampus, increased proliferation in subgranular zones, and improved the decrease in astrocytes in amnesic rats. These findings point out the anti-amnesic effects of tofisopam with concomitant improvements in the hippocampal synaptogenesis, neurogenesis, and glial plasticity, for the first time. Presented beneficial effects of tofisopam on cognitive dysfunctions may have a notable clinical value considering the fact that one of the most important side effects of 1,4-benzodiazepines, which are classical anxiolytic drugs, is amnesia. However, these preclinical results need to be confirmed with further clinical studies, first.
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