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- 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 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.
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İncele - 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.
AtıfScopus23WoS20OpenAlex22İncele