Neuropharmacology最新文献

{"title":"Effects of genetic knockdown of the serotonin transporter on established L-DOPA-induced dyskinesia and gene expression in hemiparkinsonian rats.","authors":"Grace McManus, Ashley Galfano, Carla Budrow, Natalie Lipari, Kuei Y Tseng, Fredric P Manfredsson, Christopher Bishop","doi":"10.1016/j.neuropharm.2024.110227","DOIUrl":"https://doi.org/10.1016/j.neuropharm.2024.110227","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a neurodegenerative disorder typified by the loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNpc) leading to motor symptoms including resting tremor, rigidity, akinesia, and postural instability. DA replacement therapy with levodopa (L-DOPA) remains the gold-standard treatment for the motor symptoms of PD. Unfortunately, chronic use of L-DOPA leads to the development of side effects known as L-DOPA-induced dyskinesia (LID). The mechanisms underlying LID are multifaceted, but accumulating research has strongly implicated maladaptive neuroplasticity within the raphe-striatal serotonin (5-HT) circuit. The 5-HT transporter (SERT) has emerged as an intriguing therapeutic target as it is upregulated in the brains of dyskinetic patients and animal models of LID, and pharmacological blockade of SERT alters L-DOPA's effects. Therefore, the current study employed an interventional genetic knockdown of SERT (SERT-KD) to investigate its role in LID expression and LID-associated transcription factors. To do so, hemiparkinsonian, stably dyskinetic rats (N=68) received adeno-associated virus 9 (AAV9) expressing either a short-hairpin RNA against SERT (SERT-shRNA) or a scrambled control shRNA (SCR-shRNA) after which LID reinstatement and motor performance were assayed over 2 weeks. Dorsal raphe and striatal tissue were collected for the expression analyses of known parkinsonian and LID-associated genes. Results demonstrated that SERT-KD significantly and durably reduced LID and L-DOPA-induced striatal cFOS mRNA without altering L-DOPA efficacy. Such findings point to SERT-mediated adaptations as a 5-HT mechanism by which L-DOPA exerts its actions and therapeutic target for LID.</p>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":" ","pages":"110227"},"PeriodicalIF":4.6,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"20(R)-ginsenoside Rg3 protects against focal cerebral ischemia‒reperfusion injury by suppressing autophagy via PI3K/Akt/mTOR signaling pathway.","authors":"Daiju Tao, Fajing Li, Xiaochao Zhang, Hui Guo, Renhua Yang, Yuan Yang, Li Zhang, Zhiqiang Shen, Jia Teng, Peng Chen, Bo He","doi":"10.1016/j.neuropharm.2024.110226","DOIUrl":"10.1016/j.neuropharm.2024.110226","url":null,"abstract":"<p><strong>Objective: </strong>This study aimed to investigate the effect of 20(R)-ginsenoside Rg3 on autophagy induced by cerebral ischemia‒reperfusion injury (CIRI) in rats and explore its regulation of the PI3K/Akt signaling pathway.</p><p><strong>Methods: </strong>Middle cerebral artery occlusion/reperfusion (MCAO/R) in male rats was injected intraperitoneally with 20(R)-ginsenoside Rg3 (5, 10, 20 mg/kg) 12 h before modeling, 2 h after ischemia and 12 h after reperfusion. Neurobehavioral and neuronal morphological changes were detected 24 hours after brain I/R. In vitro, the OGD/R-induced injury model is replicated in PC12 cells and different concentrations of 20(R)-ginsenoside Rg3 are administered to observe its effects on cell viability and autophagy and PI3K/Akt/mTOR-related protein expression.</p><p><strong>Results: </strong>Our findings suggest that treatment with 20 mg/kg 20(R)-ginsenoside Rg3 significantly attenuated the neuronal injury, as evidenced by a decreased number of damaged neurons, reduced dissolution of Nissl corpuscles, a fewer autophagosomes, and downregulated expression of Beclin1 and LC3-II/I compared with the MCAO/R group. Furthermore, 20(R)-ginsenoside Rg3 treatment significantly upregulated the expression of p62, p-PI3K, p-AKT, and p-mTOR. In vitro, 20(R)-ginsenoside Rg3 significantly improved the survival rate of cells following OGD/R and markedly attenuated the LY294002 and OGD/R-induced upregulation of Beclin1 and LC3 gene expression. Moreover, 20(R)-ginsenoside Rg3 could rescued the LY294002 and OGD/R-induced downregulation of p62, p-PI3K, p-AKT, and p-mTOR expression.</p><p><strong>Conclusions: </strong>20(R)-ginsenoside Rg3 attenuates neuronal injury and motor dysfunction following ischemia-reperfusion by inhibiting the activation of autophagy, and its mechanism is related to the upregulation of the PI3K/Akt/mTOR signaling pathway.</p>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":" ","pages":"110226"},"PeriodicalIF":4.6,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial DAMPs: Key Mediators in Neuroinflammation and Neurodegenerative Disease Pathogenesis.","authors":"Haihan Yu, Kaidi Ren, Yage Jin, Li Zhang, Hui Liu, Zhen Huang, Ziheng Zhang, Xing Chen, Yang Yang, Ziqing Wei","doi":"10.1016/j.neuropharm.2024.110217","DOIUrl":"10.1016/j.neuropharm.2024.110217","url":null,"abstract":"<p><p>Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are increasingly linked to mitochondrial dysfunction and neuroinflammation. Central to this link are mitochondrial damage-associated molecular patterns (mtDAMPs), including mitochondrial DNA, ATP, and reactive oxygen species, released during mitochondrial stress or damage. These mtDAMPs activate inflammatory pathways, such as the NLRP3 inflammasome and cGAS-STING, contributing to the progression of neurodegenerative diseases. This review delves into the mechanisms by which mtDAMPs drive neuroinflammation and discusses potential therapeutic strategies targeting these pathways to mitigate neurodegeneration. Additionally, it explores the cross-talk between mitochondria and the immune system, highlighting the complex interplay that exacerbates neuronal damage. Understanding the role of mtDAMPs could pave the way for novel treatments aimed at modulating neuroinflammation and slowing disease progression, ultimately improving patient outcome.</p>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":" ","pages":"110217"},"PeriodicalIF":4.6,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The synthetic cannabinoid agonist WIN 55,212-2 reduces experimental pruritus via CB₂ receptor activation.","authors":"Antonio Matt Reck, David P Siderovski, Steven G Kinsey","doi":"10.1016/j.neuropharm.2024.110216","DOIUrl":"https://doi.org/10.1016/j.neuropharm.2024.110216","url":null,"abstract":"<p><p>Pruritus (i.e., the experience that evokes a desire to scratch) is an adaptive process that can become maladaptive, leading to a persistent scratch-itch cycle that potentiates pruritus and increases the risk of infection. Cannabinoid drugs have been reported to decrease pruritus, but often at doses that also decrease locomotor activity, which confounds assessments of utility. To determine the utility of cannabinoids in treating pruritus without undesirable adverse effects, the current preclinical study investigated a range of doses of the synthetic cannabinoid agonist, WIN 55,212-2, and two minor Cannabis phytoconstituents, Δ⁸-tetrahydrocannabinol and β-caryophyllene, in experimentally induced pruritus in male and female C57BL/6J adult mice. WIN 55,212-2 reduced compound 48/80-induced scratching, and this antipruritic effect was prevented by either chemically blocking (via SR144528 antagonism) or genetically deleting the CB₂ cannabinoid receptor. The CB₂ receptor selective agonist, JWH-133, also attenuated compound 48/80-induced scratching, while the CB₁ positive allosteric modulator, ZCZ011, had no effect. Similarly, the minor phytocannabinoid Δ⁸-tetrahydrocannabinol reduced scratching at doses that did not affect locomotor activity. In contrast, the sesquiterpene cannabis constituent β-caryophyllene induced scratching, acting as a pruritogen. These preclinical data support the continuing investigation of cannabinoid receptor modulation as a potential therapeutic strategy for pruritus.</p>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":" ","pages":"110216"},"PeriodicalIF":4.6,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gallic acid and loganic acid attenuate amyloid-β oligomer-induced microglia damage via NF-КB signaling pathway","authors":"Yan-Dong Ma ,&nbsp;Hang Liu ,&nbsp;Qian Chen ,&nbsp;Yi Zheng ,&nbsp;Chao-Ren Yan ,&nbsp;Yan-Song Li ,&nbsp;Yi-Xuan Wang ,&nbsp;Yu-Ting Dai ,&nbsp;Yang-Hua Jiang ,&nbsp;Jing-Ming Shi","doi":"10.1016/j.neuropharm.2024.110215","DOIUrl":"10.1016/j.neuropharm.2024.110215","url":null,"abstract":"<div><div>Amyloid β peptide (Aβ) induces neurodegeneration in the early stage of Alzheimer's disease (AD), resulting in neuroinflammation, oxidative damage, and mitochondrial impaired function. These reactions were closely associated with the pathological changes of brain microglia. Therefore, it was crucial to investigate the precise process of neuroinflammation induced by Aβ in microglia and discover therapies to alleviate its harmful consequences. This study evaluated the toxicity detection of primary microglia generated by Aβ42 ADDL. identification of inflammatory markers, measurement of ROS, and assessment of mitochondrial energy metabolism, mitochondrial membrane potential damage and mitochondrial ROS to evaluate the reparative properties of natural small molecule compounds Gallic acid and Loganic acid on primary mouse microglia. The findings indicated that Gallic acid and Loganic acid exhibited diverse reparative effects on impaired microglia. Thus, it can be provisionally predicted that Aβ42 ADDL affects microglia and promotes modifications in the NF-кB signaling pathway. Gallic acid and Loganic acid were expected to initially restore the NF-кB signaling pathway, leading to a reduction in M1-microglia and an elevation in M2-microglia, thereby decreasing various inflammatory factors and increasing anti-inflammatory factors. The mitochondrial metabolism, mitochondrial membrane potential, and mitochondrial ROS of primary microglia were restored, leading to a reduction in neuroinflammation.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"263 ","pages":"Article 110215"},"PeriodicalIF":4.6,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624884","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MRS3997, a dual adenosine A2A/A2B receptor agonist, reduces brain ischemic damage and alleviates neuroinflammation in rats","authors":"Ilaria Dettori ,&nbsp;Irene Bulli ,&nbsp;Martina Venturini ,&nbsp;Giada Magni ,&nbsp;Federica Cherchi ,&nbsp;Francesca Rossi ,&nbsp;Hobin Lee ,&nbsp;Felicita Pedata ,&nbsp;Kenneth A. Jacobson ,&nbsp;Anna Maria Pugliese ,&nbsp;Elisabetta Coppi","doi":"10.1016/j.neuropharm.2024.110214","DOIUrl":"10.1016/j.neuropharm.2024.110214","url":null,"abstract":"<div><div>The endogenous neuromodulator adenosine is massively released during hypoxic/ischemic insults and differentially modulates post-ischemic damage depending on the expression and recruitment of its four metabotropic receptor subtypes, namely A₁, A_2A, A_2B and A₃ receptors (A₁Rs, A_2ARs, A_2BRs and A₃Rs). We previously demonstrated, by using a model of transient middle cerebral artery occlusion (tMCAo) in rats, that selective activation of A_2ARs, as well as A_2BRs, ameliorates post-ischemic brain damage in contrast to neuroinflammation. In the present study, we investigated whether the multitarget nucleoside MRS3997, a full agonist at both A_2ARs and A_2BRs, would afford higher neuroprotection in post-ischemic damage. Chronic systemic treatment with MRS3997 reduced neurological deficit, body weight loss and infarct volume in the cortex and striatum measured 7 days after ischemia. The dual agonist counteracted neuronal loss, reduced myelin damage, and prevented morphological changes indicative of microglia and astrocyte activation. Finally, MRS3997 shifted plasma cytokine levels to an anti-inflammatory profile. These effects were preceded, at 2 days after the insult, by a reduced granulocyte infiltration in the ischemic cortex and, differently from what was observed with selective A_2AR or A_2BR agonism, also in striatum.</div><div>In summary, we demonstrate here that MRS3997, systemically administered for 7 days after tMCAO, protects ischemic areas from neuronal and glial damage and inhibits neuroinflammation, therefore representing an attractive strategy to ameliorate post-stroke damage and neurological symptoms.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"262 ","pages":"Article 110214"},"PeriodicalIF":4.6,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglia-dependent peripheral neuropathic pain in adulthood following adolescent exposure to morphine in male rats","authors":"Kawsar Alami ,&nbsp;Yaghoub Fathollahi ,&nbsp;Shiva Hashemizadeh ,&nbsp;Masoumeh Mosleh ,&nbsp;Saeed Semnanian ,&nbsp;Sayed Yousof Mousavi ,&nbsp;Hossein Azizi","doi":"10.1016/j.neuropharm.2024.110211","DOIUrl":"10.1016/j.neuropharm.2024.110211","url":null,"abstract":"<div><div>Persistent effects of adolescent morphine exposure on neurobiological processes and behaviors in adulthood have been partially identified. Hypersensitivity following adolescent exposure to morphine is a complex and multifaceted phenomenon whose underlying mechanisms remain largely unknown. This study aimed to investigate the involvement of microglia in neuropathic pain sensitivity following adolescent morphine exposure, focused on hippocampal genes expression and plasticity. To achieve this, adolescent male Wistar rats received morphine, along with minocycline, to inhibit microglial activity. The allodynia and hyperalgesia of adult rats were evaluated using von-Frey filaments and the Hargreaves plantar test in both baseline and neuropathic pain conditions. Hippocampal genes expression was analyzed following the behavioral tests. The plasticity of the Schaffer-CA1 hippocampal synapses was also assessed using field potential recording following neuropathy. Results showed that adolescent morphine exposure exacerbated the allodynia and hyperalgesia in both baseline and neuropathic pain states in adult rats, which was significantly reduced by the co-administration of minocycline during adolescence. Neuropathy in adult rats was found to increase hippocampal expression of inflammatory mediators, but adolescent morphine prevented this effect. Additionally, we observed a reduction in the baseline synaptic transmission and long-term potentiation (LTP) at the Schaffer-CA1 hippocampal synapses after neuropathy in adult rats following adolescent exposure to morphine. The reduction of synaptic activity was not altered by the co-administration of minocycline with morphine during adolescence. It is concluded that microglia play an important role in mediating hypersensitivity induced by adolescent morphine exposure, although hippocampal microglia may not be directly involved in this process.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"263 ","pages":"Article 110211"},"PeriodicalIF":4.6,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nicotine and a positive allosteric modulator of m1 muscarinic receptor increase NMDA/AMPA ratio in the hippocampus and medial prefrontal cortex","authors":"Sakura Nakauchi,&nbsp;Hailing Su,&nbsp;Katumi Sumikawa","doi":"10.1016/j.neuropharm.2024.110213","DOIUrl":"10.1016/j.neuropharm.2024.110213","url":null,"abstract":"<div><div>Chronic nicotine exposure has been shown to improve memory in rodents. However, the molecular mechanism for such an enhancement remains poorly understood. Chronic nicotine exposure increases NMDA/AMPA ratio due to enhanced NMDAR-mediated responses in hippocampal CA1 pyramidal cells and facilitates LTP. Here, we found that the same nicotine treatment increases NMDA/AMPA ratios in parvalbumin-expressing interneurons in the hippocampus and in layer 5 pyramidal cells in the medial prefrontal cortex (mPFC) of male and female rats. To gain further insight into the nicotine-initiated signaling pathway, we used a positive allosteric modulator (PAM) of m1 muscarinic acetylcholine receptor (m1 receptor), VU0453595. We found that chronic VU0453595 treatment mimics the effects of chronic nicotine exposure, causing increased NMDA/AMPA ratio in hippocampal CA1 pyramidal cells and LTP facilitation. Furthermore, chronic exposure to VU0453595 also caused increased NMDA/AMPA ratio in layer 5 pyramidal cells of mPFC. As the PAM only activates m1 receptors when the endogenous agonist acetylcholine (ACh) is present, the findings suggest that the release of ACh from cholinergic neurons is involved in the effect. Thus, chronic nicotine exposure, by increasing ACh release, may stimulate a signaling pathway in various neuron types, which receive cholinergic input and express m1 receptors, leading to the enhancement of NMDAR responses. The nicotine-initiated signaling pathway, in which ACh and m1 receptors are downstream of nicotinic ACh receptor activation, may represent an important cholinergic pathway involved in cognitive function.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"262 ","pages":"Article 110213"},"PeriodicalIF":4.6,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The engagement of Ras/Raf/MEK/ERK and PLCγ1/PKC pathways regulated by TrkB receptor in resistance of glioma cells to elimination upon apoptosis induction","authors":"Adrian Zając ,&nbsp;Joanna Sumorek-Wiadro ,&nbsp;Aleksandra Maciejczyk ,&nbsp;Michał Chojnacki ,&nbsp;Iwona Wertel ,&nbsp;Wojciech Rzeski ,&nbsp;Joanna Jakubowicz-Gil","doi":"10.1016/j.neuropharm.2024.110204","DOIUrl":"10.1016/j.neuropharm.2024.110204","url":null,"abstract":"<div><div>The most aggressive tumors of human central nervous system are anaplastic astrocytoma (AA, III grade) and glioblastoma multiforme (GBM, IV grade) with an extremely bad prognosis. Their malignant character and resistance to standard therapy are correlated to the over-expression of survival pathways such as Ras/Raf/MEK/ERK and PLCγ1/PKC regulated by TrkB receptor. Therefore, the aim of this study was to investigate the engagement of those pathways in human glioma cells resistance for apoptosis induction by Temozolomide treatment. Two cancer MOGGCCM (AA) and T98G (GBM) and normal human astrocytes (NHA) cell lines were utilized. The tested inhibitors single and simultaneous action with Temozolomide affection on apoptosis induction was analyzed by MTT, microscopic observations and flow cytometry. Bcl-2:beclin-1 complexes occurrence was also assessed. siRNAs were used for direct proof of tested pathways engagement in gliomas resistance to apoptosis elimination. The most effective in eliminating gliomas with minimal astrocyte damage was 5 μM PLCγ1 inhibitor (U-73122) for MOGGCCM and 15 μM for T98G cells, and 1 μM LOXO-101 for all cancer cells. Sorafenib, Temozolomide, U-73122, and LOXO-101 effectively eliminate cancer cells. Single applications of sorafenib and Temozolomide were effective, but had lower efficiency than U-73122 and LOXO-101. These drugs induced apoptosis, affecting mitochondrial membrane potential and caspases 3, 8, and 9 activity. The study found that a Bcl-2:beclin-1 complex formation was observed when apoptosis was dominant. Inhibiting the pathways regulated by TrkB receptor combined with Temozolomide action, led to successful gliomas elimination. Those results might serve as basis for modern targeted treatment development.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"262 ","pages":"Article 110204"},"PeriodicalIF":4.6,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ferroptosis and cognitive impairment: Unraveling the link and potential therapeutic targets","authors":"Soudabeh Naderi ,&nbsp;Fariba Khodagholi ,&nbsp;Mahyar Janahmadi ,&nbsp;Fereshteh Motamedi ,&nbsp;Abolfazl Torabi ,&nbsp;Zehra Batool ,&nbsp;Mahshad Fadaeimoghadam Heydarabadi ,&nbsp;Hamid Gholami Pourbadie","doi":"10.1016/j.neuropharm.2024.110210","DOIUrl":"10.1016/j.neuropharm.2024.110210","url":null,"abstract":"<div><div>Neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases, share key characteristics, notably cognitive impairment and significant cell death in specific brain regions. Cognition, a complex mental process allowing individuals to perceive time and place, is disrupted in these conditions. This consistent disruption suggests the possibility of a shared underlying mechanism across all neurodegenerative diseases. One potential common factor is the activation of pathways leading to cell death. Despite significant progress in understanding cell death pathways, no definitive treatments have emerged. This has shifted focus towards less-explored mechanisms like ferroptosis, which holds potential due to its involvement in oxidative stress and iron metabolism. Unlike apoptosis or necrosis, ferroptosis offers a novel therapeutic avenue due to its distinct biochemical and genetic underpinnings, making it a promising target in neurodegenerative disease treatment. Ferroptosis is distinguished from other cellular death mechanisms, by distinctive characteristics such as an imbalance of iron hemostasis, peroxidation of lipids in the plasma membrane, and dysregulated glutathione metabolism. In this review, we discuss the potential role of ferroptosis in cognitive impairment. We then summarize the evidence linking ferroptosis biomarkers to cognitive impairment brought on by neurodegeneration while highlighting recent advancements in our understanding of the molecular and genetic mechanisms behind the condition. Finally, we discuss the prospective therapeutic implications of targeting ferroptosis for the treatment of cognitive abnormalities associated with neurodegeneration, including natural and synthetic substances that suppress ferroptosis via a variety of mechanisms. Promising therapeutic candidates, including antioxidants and iron chelators, are being explored to inhibit ferroptosis and mitigate cognitive decline.</div></div>","PeriodicalId":19139,"journal":{"name":"Neuropharmacology","volume":"263 ","pages":"Article 110210"},"PeriodicalIF":4.6,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}