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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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    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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    Effect of Reboxetine Treatment on BDNF, Synaptophysin, and PSD-95 Levels in the Spinal Dorsal Horn of Rats with Diabetic Neuropathy
    (Marmara Univ, Inst Health Sciences, 2023) Yucel, Nazli Turan; Ucel, Umut Irfan; Ozkay, Umide Demir; Ulupinar, Emel; Can, Ozgur Devrim
    Objective: It is known that neuropathic pain is accompanied by alterations in the levels of neurotrophic factors and synaptic proteins in the microenvironment of the spinal dorsal horn. Such changes contribute to hyperalgesia and allodynia processes; thus, analgesic drugs can exert their pharmacological effects by affecting the expressions, levels, or functions of these endogenous substances. In this study, based on the knowledge that reboxetine (a selective noradrenaline reuptake inhibitor) has the potential for antihyperalgesic efficacy in diabetic neuropathy, we aimed to examine the probable effects of this drug on diabetes-induced changes in brain-derived neurotrophic factor (BDNF), synaptophysin (the pre-synaptic marker of synaptic integration), and postsynaptic density-95 (PSD-95) (the postsynaptic marker of synaptic integration) levels in the superficial laminae of the dorsal horn.Methods: Experimental diabetes was induced by a single-dose injection of streptozotocin (STZ) (50 mg/kg) in rats. After four week-long induction period of painful diabetic neuropathy, rats were treated orally with 8 mg/kg reboxetine for two weeks. Hyperalgesia responses were evaluated by using the Randall-Selitto and Hargreave's tests. Following the pain tests, immunohistochemical studies were performed.Results: Two weeks of reboxetine administration increased the reduced paw withdrawal thresholds and shortened the paw withdrawal latencies of diabetic rats in neuropathic pain tests, indicating the antihyperalgesic efficacy of this drug. Moreover, augmented BDNF and synaptophysin levels in diabetic rats reversed by reboxetine treatment. However, there was no alteration in the densities of PSD-95, in both STZ-diabetic and reboxetine-treated STZ-diabetic rats.Conclusion: The obtained results suggested that inhibition of central sensitization and modulation of spinal plasticity seem to be pharmacological mechanisms underlying reboxetine's antihyperalgesic effects on diabetic rats. However, further studies are still needed to clarify the exact mechanism of action.