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    Beneficial Effect of Atomoxetine Treatment on Scopolamine-Induced Cognitive Impairments and Molecular Changes in Rats
    (Yerkure Tanitim & Yayincilik Hizmetleri A S, 2023) Yucel, Nazli Turan; Ucel, Umut Irfan; Kandemir, Ummuhan; Can, Ozgur Devrim
    Objective: Atomoxetine is a noradrenaline re-uptake inhibitory drug that is currently used in the pharmacological treatment of attention deficit/hyperactivity disorder in children, adolescents, and adults. Based on the findings that noradrenergic system is closely associated with learning and memory processes, dysfunction of this system might contribute to the pathophysiology of cognitive disorders. Therefore, atomoxetine, which alters the noradrenergic neurotransmission in the synaptic cleft, has a potential to modulate learning and memory functions in various areas of the central nervous system. In the present study, it was aimed to investigate the effects of atomoxetine treatment on the cognitive impairments in amnesic animals using behavioral and immunohistochemical methods.Methods: Male Sprague-Dawley rats (adult, weighing 250-300 g) were used in the experiments. Atomoxetine at doses of 3 or 6 mg/kg (i.p.) was administered to the rats for 14 days. Experimental amnesia was induced in the animals by applying scopolamine (0.5 mg/kg, i.p.) injection. Following the treatment protocol, Morris water maze and passive avoidance tests were conducted to assess spatial and emotional learning and memory parameters of rats, respectively. Piracetam (300 mg/kg daily for 14 days) was used as reference drug in these experiments. In addition, motor performances of the animals were evaluated by activity cage and Rota-rod tests. Subsequent to behavioral tests, rats were euthanized and immunohistochemical analyses were performed to determine the alterations in the brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels in the hippocampi of the animals.Results: In the Morris water maze test, amnesic rats found the hidden platform slower and spent less time in the target quadrant compared to the healthy controls. On the other hand, atomoxetine treatments significantly decreased the escape latencies, and also increased the target quadrant time values of the amnesic animals at both doses. Data obtained from the passive avoidance test showed that second transition latency values of the amnesic rats were significantly shortened with respect to the control animals; while atomoxetine treatment prolonged these shortened values significantly. It was observed that atomoxetine did not alter motor coordination or spontaneous locomotor activities of animals. Moreover, this drug increased the BDNF and NGF levels in the hippocampal sub-regions which were diminished by scopolamine administration.Conclusion: The obtained findings showed that atomoxetine treatment significantly improved the impaired learning and memory performances of the rats induced by scopolamine administration. Furthermore, anti-amnesic effects of this drug were concomitant with increased neurotrophic factors levels in the hippocampal brain regions. These results suggest a notable therapeutic potential of this drug in the treatment of dementia and several cognitive disorders; however, it should be underlined they are needed to be confirmed by welldesigned clinical trials.
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    Catecholaminergic and Cholinergic Systems Mediate Beneficial Effect of Vortioxetine on Diabetes-Induced Neuropathic Pain
    (Mdpi, 2023) Turan Yucel, Nazli; Kandemir, Ummuhan; Ucel, Umut Irfan; Ozkay, Umide Demir; Can, Ozgur 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, alpha(2)- and beta(2)-adrenoceptors, D-2/3 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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    Cognitive improvement and hippocampal BDNF/GFAP alterations by Schinus molle essential oil in a rat model of scopolamine-induced amnesia
    (Elsevier Ireland Ltd, 2026) Ucel, Umut Irfan; Kandemir, Ummuhan; Yazici, Cevsen; Bilgin, Oznur; Yucel, Nazli Turan; Ozek, Temel; Can, Ozgur Devrim
    Ethnopharmacological relevance Schinus 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 study To 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 methods SMEO 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. Results SMEO was dominated by alpha-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. Conclusions These 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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    Subacute ivermectin-induced affective dysregulation: Evidence for hippocampal microglial and astrocytic activation
    (Elsevier Sci Ltd, 2026) Eser, Mustafa; Yazic, Cevsen; Kandemir, Ummuhan; Ucel, Umut Irfan; Bozkurt, Mehmet Fatih; Ozkay, Umide Demir; Can, Ozgur 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.