Deepti Mudaliar, Rachel H Mansky, Angel White, Grace Baudhuin, Jon Hawkinson, Henry Wong, Michael A Walters, Rocio Gomez-Pastor
Protein kinase CK2 is a holoenzyme composed of two regulatory subunits (CK2β) and two catalytic subunits (CK2α and CK2α'). CK2 controls several cellular processes, including proliferation, inflammation, and cell death. However, CK2α and CK2α' possess different expression patterns and substrates and therefore impact each of these processes differently. Elevated CK2α participates in the development of cancer, while increased CK2α' has been associated with neurodegeneration, especially Huntington's disease (HD)...
June 22, 2024: ACS Chemical Neuroscience
Meiyan Xian, Jingwen Li, Tingting Liu, Kaiying Hou, Lin Sun, Jianshe Wei
Parkinson's disease (PD) is the second most common age-related neurodegenerative disease in the world, and synuclein is closely related to the onset and progression of PD. Synuclein is considered a therapeutic target for PD. Recent studies have found that abnormal aggregation of α-synuclein (α-Syn) in the brains of PD patients leads to mitochondrial dysfunction and neuroinflammation. Research in the field of neuroscience has confirmed that β-synuclein (β-Syn) also plays a role in Parkinson's disease...
June 21, 2024: ACS Chemical Neuroscience
Kalyani Soren, Rakesh K Bollikanda, Tapatee Das, Shashikant Patel, Kodi Gnaneshwari, Pankaj Malakar, Arvind Kumar, Srinivas Kantevari, Sumana Chakravarty
Chronic hypoxic exposure triggers the onset and progression of cognitive dysfunction; however, the mechanisms underlying chronic hypoxia-induced neuroinflammation and its contribution to cognitive dysfunction remain poorly understood. Although inflammation and hypoxia are interdependent, numerous recent studies have linked the development of various human diseases to hypoxia-induced inflammation. In this study, we focused on the NLRP3 inflammasome with novel analogues of cytokine release inhibitory drug 3 (CRID3), a class of small molecule inhibitors for the NLRP3 inflammasome, to investigate their potential contribution to alleviating chronic hypoxia-induced neuroinflammation using the zebrafish model...
June 20, 2024: ACS Chemical Neuroscience
Kritika Bhardwaj, Aditya A Singh, Hemant Kumar
Parkinson's disease, a classical motor disorder affecting the dopaminergic system of the brain, has been as a disease of the brain, but this classical notion has now been viewed differently as the pathology begins in the gut and then gradually moves up to the brain regions. The microorganisms in the gut play a critical role in maintaining the physiology of the gut from maintaining barrier integrity to secretion of microbial products that maintain a healthy gut state. The pathology subsequently alters the normal composition of gut microbes and causes deleterious effects that ultimately trigger strong neuroinflammation and nonmotor symptoms along with characteristic synucleopathy, a pathological hallmark of the disease...
June 19, 2024: ACS Chemical Neuroscience
Sébastien Goutal, Thi Tran, Claire Leroy, Nadine Benhamouda, Sarah Leterrier, Wadad Saba, Bruno Lafont, Éric Tartour, Marie Roelens, Nicolas Tournier
Neuroimaging biomarkers are needed to investigate the impact of smoking withdrawal on brain function. NFL-101 is a denicotinized aqueous extract of tobacco leaves currently investigated as an immune-based smoking cessation therapy in humans. However, the immune response to NFL-101 and its ability to induce significant changes in brain function remain to be demonstrated. Brain glucose metabolism was investigated using [18 F]fluoro-deoxy-glucose ([18 F]FDG) PET imaging in a mouse model of cigarette smoke exposure (CSE, 4-week whole-body inhalation, twice daily)...
June 14, 2024: ACS Chemical Neuroscience
Prabir Kumar Gharai, Juhee Khan, Krishnangsu Pradhan, Rathnam Mallesh, Shubham Garg, Mohammad Umar Arshi, Surajit Barman, Surajit Ghosh
In Alzheimer's disease (AD), reactive oxygen species (ROS) plays a crucial role, which is produced from molecular oxygen with extracellular deposited amyloid-β (Aβ) aggregates through the reduction of a Cu2+ ion. In the presence of a small amount of redox-active Cu2+ ion, ROS is produced by the Aβ-Cu2+ complex as Aβ peptide alone is unable to generate excess ROS. Therefore, Cu2+ ion chelators are considered promising therapeutics against AD. Here, we have designed and synthesized a series of Schiff base derivatives (SB) based on 2-hydroxy aromatic aldehyde derivatives and dopamine...
June 14, 2024: ACS Chemical Neuroscience
Yuting Zhao, Yan Peng, Xiuzhen Wei, Genping Wu, Bo Li, Xuelin Li, Lin Long, Jing Zeng, Wei Luo, Ying Tian, Zhen Wang, Xue Peng
Neuroinflammation is an important factor that exacerbates neuronal death and abnormal synaptic function in neurodegenerative diseases (NDDs). Due to the complex pathogenesis and the presence of blood-brain barrier (BBB), no effective clinical drugs are currently available. Previous results showed that N -salicyloyl tryptamine derivatives had the potential to constrain the neuroinflammatory process. In this study, 30 new N -salicyloyl tryptamine derivatives were designed and synthesized to investigate a structure-activity relationship (SAR) for the indole ring of tryptamine in order to enhance their antineuroinflammatory effects...
June 12, 2024: ACS Chemical Neuroscience
Caleb A H Jones, Benjamin P Brown, Daniel C Schultz, Julie Engers, Valerie M Kramlinger, Jens Meiler, Craig W Lindsley
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra, resulting in motor dysfunction. Current treatments are primarily centered around enhancing dopamine signaling or providing dopamine replacement therapy and face limitations such as reduced efficacy over time and adverse side effects. To address these challenges, we identified selective dopamine receptor subtype 4 (D4 R) antagonists not previously reported as potential adjuvants for PD management...
June 7, 2024: ACS Chemical Neuroscience
Eun Young Jang, Bong Hyo Lee, Jaesuk Yun, Chae Ha Yang, Seong Shoon Yoon
Recently, the abuse of synthetic cathinones is increasing among young people. α-Pyrrolidinobutiothiophenone (α-PBT), a synthetic cathinone, is a designer drug that is freely traded online with no legal restrictions. Moreover, there is currently no scientific basis for legal regulation. Here, we examined the addictive properties of α-PBT using a drug discrimination (DD) task. We also investigated the role of α-PBT in brain stimulation reward (BSR) using an intracranial self-stimulation (ICSS) paradigm in rats...
June 5, 2024: ACS Chemical Neuroscience
Rathnam Mallesh, Juhee Khan, Prabir Kumar Gharai, Mohammad Umar Arshi, Shubham Garg, Sanju Gupta, Surajit Ghosh
Spontaneous aggregation of amyloid beta (Aβ) leads to the formation of neurotoxic senile plaque considered as the most crucial event in Alzheimer's disease (AD) progression. Inhibition or disruption of this deadly aggregate formation is one of the most efficient strategies for the development of potential therapeutics, and extensive research is in progress by various research groups. In this direction, the development of a peptide analogous to that of the native Aβ peptide is an attractive strategy...
June 1, 2024: ACS Chemical Neuroscience
Alexandru Graur, Amanda Haymond, Kyung Hyeon Lee, Franco Viscarra, Paul Russo, Alessandra Luchini, Mikell Paige, Isabel Bermudez-Diaz, Nadine Kabbani
Nicotinic acetylcholine receptors (nAChRs) are a family of ligand-gated ion channel receptors that contribute to cognition, memory, and motor control in many organisms. The pharmacological targeting of these receptors, using small molecules or peptides, presents an important strategy for the development of drugs that can treat important human diseases, including neurodegenerative disorders. The Aplysia californica acetylcholine binding protein (Ac-AChBP) is a structural surrogate of the nAChR with high homology to the extracellular ligand binding domain of homopentameric nAChRs...
May 28, 2024: ACS Chemical Neuroscience
Naveen Kumar, Kailash Jangid, Vishal Kumar, Ravi Prakash Yadav, Jayapriya Mishra, Shubham Upadhayay, Vinay Kumar, Bharti Devi, Vijay Kumar, Ashish Ranjan Dwivedi, Puneet Kumar, Somesh Baranwal, Jasvinder Singh Bhatti, Vinod Kumar
Alzheimer's disease is a complex neurological disorder linked with multiple pathological hallmarks. The interrelation of therapeutic targets assists in the enhancement of cognitive decline through interference with overall neuronal transmission. We have synthesized and screened various chromone derivatives as potential multitarget-directed ligands for the effective treatment of Alzheimer's disease. The synthesized compounds exhibited multipotent activity against AChE, BuChE, MAO-B, and amyloid β aggregation...
May 25, 2024: ACS Chemical Neuroscience
Akash Kumar Singh, Amrish Rai, Ila Joshi, Damodara N Reddy, Rajdeep Guha, Kumari Alka, Shubha Shukla, Srikanta Kumar Rath, Aamir Nazir, James P Clement, Tapas K Kundu
TTK21 is a small-molecule activator of p300/creb binding protein (CBP) acetyltransferase activity, which, upon conjugation with a glucose-derived carbon nanosphere (CSP), can efficiently cross the blood-brain barrier and activate histone acetylation in the brain. Its role in adult neurogenesis and retention of long-term spatial memory following intraperitoneal (IP) administration is well established. In this study, we successfully demonstrate that CSP-TTK21 can be effectively administered via oral gavage. Using a combination of molecular biology, microscopy, and electrophysiological techniques, we systematically investigate the comparative efficacy of oral administration of CSP and CSP-TTK21 in wild-type mice and evaluate their functional effects in comparison to intraperitoneal (IP) administration...
May 25, 2024: ACS Chemical Neuroscience
Alexander J Dear, Dev Thacker, Stefan Wennmalm, Lei Ortigosa-Pascual, Ewa A Andrzejewska, Georg Meisl, Sara Linse, Tuomas P J Knowles
Oligomeric assemblies consisting of only a few protein subunits are key species in the cytotoxicity of neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases. Their lifetime in solution and abundance, governed by the balance of their sources and sinks, are thus important determinants of disease. While significant advances have been made in elucidating the processes that govern oligomer production, the mechanisms behind their dissociation are still poorly understood. Here, we use chemical kinetic modeling to determine the fate of oligomers formed in vitro and discuss the implications for their abundance in vivo...
May 24, 2024: ACS Chemical Neuroscience
Wan-Ying Liu, Yang Yu, Juan Zang, Yang Liu, Feng-Rui Li, Lu Zhang, Rui-Bo Guo, Liang Kong, Ling-Yue Ma, Xue-Tao Li
Oxidative stress and neuroinflammation in the aging brain are correlated with the development of neurodegenerative diseases, such as Alzheimer's disease (AD). The blood-brain barrier (BBB) poses a significant challenge to the effective delivery of therapeutics for AD. Prior research has demonstrated that menthol (Men) can augment the permeability of the BBB. Consequently, in the current study, we modified Men on the surface of liposomes to construct menthol-modified quercetin liposomes (Men-Qu-Lips), designed to cross the BBB and enhance quercetin (Qu) concentration in the brain for improved therapeutic efficacy...
May 23, 2024: ACS Chemical Neuroscience
Ying Zhou, Ting Qi, Yuwei Yang, Zhihui Li, Zhuoran Hou, Xiangwei Zhao, Qinyu Ge, Zuhong Lu
Staining frozen sections is often required to distinguish cell types for spatial transcriptomic studies of the brain. The impact of the staining methods on the RNA integrity of the cells becomes one of the limitations of spatial transcriptome technology with microdissection. However, there is a lack of systematic comparisons of different staining modalities for the pretreatment of frozen sections of brain tissue as well as their effects on transcriptome sequencing results. In this study, four different staining methods were analyzed for their effect on RNA integrity in frozen sections of brain tissue...
May 23, 2024: ACS Chemical Neuroscience
Yanyan Kong, Lei Cao, Jiao Wang, Junyi Zhuang, Yongshan Liu, Lei Bi, Yifan Qiu, Yuyi Hou, Qi Huang, Fang Xie, Yunhao Yang, Kuangyu Shi, Axel Rominger, Yihui Guan, Hongjun Jin, Ruiqing Ni
Neuroinflammation plays an important role in Alzheimer's disease and primary tauopathies. The aim of the current study was to map [18 F]GSK1482160 for imaging of purinergic P2X7R in Alzheimer's disease and primary tauopathy mouse models. Small animal PET was performed using [18 F]GSK1482160 in widely used mouse models of Alzheimer's disease (APP/PS1, 5×FAD, and 3×Tg), 4-repeat tauopathy (rTg4510) mice, and age-matched wild-type mice. Increased uptake of [18 F]GSK1482160 was observed in the brains of 7-month-old rTg4510 mice compared to wild-type mice and compared to 3-month-old rTg4510 mice...
May 22, 2024: ACS Chemical Neuroscience
Zhen Liu, Xuan Luo, Richard Yan-Do, Yuan Wang, Xi Xie, Zhongping Li, Shuk Han Cheng, Peng Shi
Mapping brain activities is necessary for understanding brain physiology and discovering new treatments for neurological disorders. Such efforts have greatly benefited from the advancement in technologies for analyzing neural activity with improving temporal or spatial resolution. Here, we constructed a multielectrode array based brain activity mapping (BAM) system capable of stabilizing and orienting zebrafish larvae for recording electroencephalogram (EEG) like local field potential (LFP) signals and brain-wide calcium dynamics in awake zebrafish...
May 22, 2024: ACS Chemical Neuroscience
Ankita Jaiswal, Monisha Patel, Anam Naseer, Simran Kumari, Neeraja Revi, Aravind Rengan, Alok Jain, Aamir Nazir, Nidhi Gour, Sandeep Verma
The aggregation of amino acids into amyloid-like structures is a critical phenomenon for understanding the pathophysiology of various diseases, including inborn errors of metabolism (IEMs) associated with amino acid imbalances. Previous studies have primarily focused on self-assembly of aromatic amino acids, leading to a limited understanding of nonaromatic, polar amino acids in this context. To bridge this gap, our study investigates the self-assembly and aggregation behavior of specific nonaromatic charged and uncharged polar amino acids l-glutamine (Gln), l-aspartic acid (Asp), and l-glutamic acid (Glu), which have not been reported widely in the context of amyloid aggregation...
May 20, 2024: ACS Chemical Neuroscience
Eric Sparkes, Callan J Maloney, Jack W Markham, Chianna Dane, Rochelle Boyd, Jayson Gilchrist, Michael Moir, Rebecca Gordon, Jia Lin Luo, Edward Pike, Katelyn A Walker, Michael Kassiou, Iain S McGregor, Richard C Kevin, David E Hibbs, William T Jorgensen, Samuel D Banister, Elizabeth A Cairns, Adam Ametovski
Synthetic cannabinoid receptor agonists (SCRAs) are a growing class of new psychoactive substances (NPS) commonly derived from an N -alkylated indole, indazole, or 7-azaindole scaffold. Diversification of this core (at the 3-position) with amide-linked pendant amino acid groups and modular N -alkylation (of the indole/indazole/7-azaindole core) ensures that novel SCRAs continue to enter the illicit drug market rapidly. In response to the large number of SCRAs that have been detected, pharmacological evaluation of this NPS class has become increasingly common...
May 20, 2024: ACS Chemical Neuroscience
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