Browsing by Subject "NEUROTOXICITY"

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  • Grotell, Milo; den Hollander, Bjornar; Jalkanen, Aaro; Törrönen, Essi; Ihalainen, Jouni; de Miguel, Elena; Dudek, Mateusz; Kettunen, Mikko I.; Hyytiä, Petri; Forsberg, Markus M.; Kankuri, Esko; Korpi, Esa R. (2021)
    Mephedrone (4-MMC), despite its illegal status, is still a widely used psychoactive substance. Its effects closely mimic those of the classical stimulant drug methamphetamine (METH). Recent research suggests that unlike METH, 4-MMC is not neurotoxic on its own. However, the neurotoxic effects of 4-MMC may be precipitated under certain circumstances, such as administration at high ambient temperatures. Common use of 4-MMC in conjunction with alcohol raises the question whether this co-consumption could also precipitate neurotoxicity. A total of six groups of adolescent rats were treated twice daily for four consecutive days with vehicle, METH (5 mg/kg) or 4-MMC (30 mg/kg), with or without ethanol (1.5 g/kg). To investigate persistent delayed effects of the administrations at two weeks after the final treatments, manganese-enhanced magnetic resonance imaging brain scans were performed. Following the scans, brains were collected for Golgi staining and spine analysis. 4-MMC alone had only subtle effects on neuronal activity. When administered with ethanol, it produced a widespread pattern of deactivation, similar to what was seen with METH-treated rats. These effects were most profound in brain regions which are known to have high dopamine and serotonin activities including hippocampus, nucleus accumbens and caudate-putamen. In the regions showing the strongest activation changes, no morphological changes were observed in spine analysis. By itself 4-MMC showed few long-term effects. However, when co-administered with ethanol, the apparent functional adaptations were profound and comparable to those of neurotoxic METH.
  • Leino, Sakari; Koski, Sini K.; Hänninen, Raisa; Tapanainen, Tuukka; Rannanpää, Saara; Salminen, Outi (2018)
    Preclinical studies suggest the involvement of various subtypes of nicotinic acetylcholine receptors in the pathophysiology of Parkinson's disease, a neurodegenerative disorder characterized by the death of dopaminergic neurons in the substantia nigra pars compacta (SNC). We studied for the first time the effects of alpha 5 nicotinic receptor subunit gene deletion on motor behavior and neurodegeneration in mouse models of Parkinson's disease and levodopa-induced dyskinesia. Unilateral dopaminergic lesions were induced in wild-type and alpha 5-KO mice by 6-hydroxydopamine injections into the striatum or the medial forebrain bundle. Subsequently, rotational behavior induced by dopaminergic drugs was measured. A subset of animals received chronic treatments with levodopa and nicotine to assess levodopa-induced dyskinesia and antidyskinetic effects by nicotine. SNC lesion extent was assessed with tyrosine hydroxylase immunohistochemistry and stereological cell counting. Effects of alpha 5 gene deletion on the dopaminergic system were investigated by measuring ex vivo striatal dopamine transporter function and protein expression, dopamine and metabolite tissue concentrations and dopamine receptor mRNA expression. Hemiparkinsonian alpha 5-KO mice exhibited attenuated rotational behavior after amphetamine injection and attenuated levodopa-induced dyskinesia. In the intrastriatal lesion model, dopaminergic cell loss in the medial cluster of the SNC was less severe in alpha 5-KO mice. Decreased striatal dopamine uptake in alpha 5-KO animals suggested reduced dopamine transporter function as a mechanism of attenuated neurotoxicity. Nicotine reduced dyskinesia severity in wild-type but not alpha 5-KO mice. The attenuated dopaminergic neurodegeneration and motor dysfunction observed in hemiparkinsonian alpha 5KO mice suggests potential for alpha 5 subunit-containing nicotinic receptors as a novel target in the treatment of Parkinson's disease. (C) 2018 The Authors. Published by Elsevier Ltd.
  • Kauppila, Esa; Vanninen, Esko; Kaurijoki, Salla; Karhunen, Leila; Pietiläinen, Kirsi Hannele; Rissanen, Aila; Tiihonen, Jari; Pesonen, Ullamari; Kaprio, Jaakko (2013)
  • Valtonen, Jussi; Karrasch, Mira (2020)
    Polypharmacy is common in patients with a diagnosis of bipolar disorder. Although polypharmacy is known to increase the risk of iatrogenic neurological conditions, the recovery of cognitive function after drug withdrawal has been rarely documented in psychiatric patients using standardized neuropsychological methods. We present a neuropsychological case report of patient SN, a 41-year-old woman who developed a socially and occupationally detrimental condition of cognitive dysfunction likely induced by long-term exposure to lithium and other psychiatric medications. To shed light on SN’s cognitive deficits and their recovery after drug withdrawal, neuropsychological assessments were conducted before, and approximately 2 years after, lithium and other psychiatric drugs were discontinued. Selective cognitive impairments were observed before drug discontinuation in visuomotor speed, visuoperceptual reasoning and delayed visual memory. Partial, but not complete, recovery of function was observed 2 years after drug withdrawal.
  • Maleki, Reza; Khedri, Mohammad; Rezvantalab, Sima; Afsharchi, Fatemeh; Musaie, Kiyan; Shafiee, Sepehr; Shahbazi, Mohammad-Ali (2021)
    Cytotoxic aggregation of misfolded beta-amyloid (A beta) proteins is the main culprit suspected to be behind the development of Alzheimer's disease (AD). In this study, A beta interactions with the novel two-dimensional (2D) covalent organic frameworks (COFs) as therapeutic options for avoiding beta-amyloid aggregation have been investigated. The results from multi-scale atomistic simulations suggest that amine-functionalized COFs with a large surface area (more than 1000 m(2)/gr) have the potential to prevent A beta aggregation. Gibb's free energy analysis confirmed that COFs could prevent protofibril self-assembly in addition to inhibiting beta-amyloid aggregation. Additionally, it was observed that the amine functional group and high contact area could improve the inhibitory effect of COFs on A beta aggregation and enhance the diffusivity of COFs through the blood-brain barrier (BBB). In addition, microsecond coarse-grained (CG) simulations with three hundred amyloids reveal that the presence of COFs creates instability in the structure of amyloids and consequently prevents the fibrillation. These results suggest promising applications of engineered COFs in the treatment of AD and provide a new perspective on future experimental research.