ACS Chemical Neuroscience最新文献

{"title":"Determinants for Substoichiometric Inhibition of IAPP and Aβ Amyloid Aggregations by Bri2 BRICHOS","authors":"Zhenzhen Zhang,&nbsp;Gangtong Huang,&nbsp;Shivani Gupta,&nbsp;Emma Sargent,&nbsp;Huayuan Tang* and Feng Ding*,&nbsp;","doi":"10.1021/acschemneuro.4c0083910.1021/acschemneuro.4c00839","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00839https://doi.org/10.1021/acschemneuro.4c00839","url":null,"abstract":"<p >Bri2 BRICHOS, a folded domain of the transmembrane protein Bri2 expressed in both the brain and pancreas, is an experimentally known substoichiometric inhibitor of amyloid aggregation. The molecular chaperone effectively delays fibrillization at low molar ratios for both β-amyloid (Aβ) in Alzheimer’s disease (AD) and islet amyloid polypeptide (IAPP) in type 2 diabetes (T2D). While discovering effective antiamyloid inhibitors that work at low doses is an appealing strategy to mitigate amyloid toxicity, the molecular mechanism underlying the broad and efficient antiamyloid activity of Bri2 BRICHOS remains unknown. Here, we computationally demonstrated that Bri2 BRICHOS exhibits a stronger binding affinity to fibril seeds than to monomers using atomistic discrete molecular dynamic simulations. By competing with monomers to bind the active elongation sites on newly nucleated, weakly populated fibril seeds, a small amount of Bri2 BRICHOS could block rapid fibril growth via monomer addition. The experimentally observed differential inhibition efficiency against IAPP and Aβ aggregation was found to depend on the relative fibril-binding affinities of the inhibitor compared to those of self-seeding monomers. Our computationally derived determinants for substoichiometric inhibition against amyloid aggregation by Bri2 BRICHOS may inform the future design of potent antiamyloid therapies for AD, T2D, and other amyloid diseases.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 6","pages":"1150–1160 1150–1160"},"PeriodicalIF":4.1,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143641536","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Monoamine Oxidase Inhibitors Present in Tobacco Modulate Dopamine Balance Via the Dopamine Transporter","authors":"Gabriella Saro*,&nbsp;Stephanie Johne,&nbsp;Diogo A.R.S. Latino,&nbsp;Fabian Moine,&nbsp;Marco van der Toorn,&nbsp;Carole Mathis and Emilija Veljkovic,&nbsp;","doi":"10.1021/acschemneuro.4c0078910.1021/acschemneuro.4c00789","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00789https://doi.org/10.1021/acschemneuro.4c00789","url":null,"abstract":"<p >It has been reported that nicotine affects brain dopamine homeostasis. By binding to nicotinic acetylcholine receptors, including those expressed by dopaminergic neurons of the ventral tegmental area, nicotine stimulates dopamine release and signaling. Dopamine is taken up from the synaptic cleft by the dopamine transporter (DAT) into presynaptic neurons, where it is degraded by monoamine oxidase (MAO). Besides nicotine, other tobacco compounds play a role in dopamine modulation. To better understand the biological effects of nicotine and other tobacco compounds on dopamine regulation, we selected a group of tobacco compounds based on their potential affinity to bind human MAO-A and MAO-B enzymes using an <i>in silico</i> approach. Subsequently, we tested the putative compounds in an enzymatic assay to verify their ability to inhibit human MAO-A or MAO-B. The positive hits were harman, norharman, harmaline, and 1-ethyl-β-carboline. While harman and norharman have been extensively studied, both harmaline and 1-ethyl-β-carboline have not been described in the context of tobacco and MAO inhibition before. We investigated DAT activity in an overexpressing cell line and dopamine release and uptake in rat striatal synaptosomes. We clearly demonstrate that tested MAO-A inhibitors (MAO-AIs) significantly attenuated human DAT activity and consequent dopamine uptake, establishing a functional connection between MAOIs and dopamine uptake via DAT. Interestingly, the tested MAO-AIs elicited pronounced dopamine release in crude synaptosomal preparations. In summary, this <i>in vitro</i> study demonstrates that tested MAO-AIs found in cigarette smoke not only reduce MAO activity but also strongly impact dopamine homeostatic mechanisms via DAT. Further <i>in vivo</i> investigations would advance our understanding of the underlying mechanisms of dopamine regulation and homeostasis.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 6","pages":"1117–1131 1117–1131"},"PeriodicalIF":4.1,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acschemneuro.4c00789","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143641215","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acridine Benzimidazolium Derivatives Induced Protective Microglia Polarization and In Silico TDP-43 Interaction─Potential Implications for Amyotrophic Lateral Sclerosis","authors":"Neeraja Revi,&nbsp;Muneshwar Nandeshwar,&nbsp;Dinesh Harijan,&nbsp;Sri Amruthaa Sankaranarayanan,&nbsp;Meet Joshi,&nbsp;Ganesan Prabusankar* and Aravind Kumar Rengan*,&nbsp;","doi":"10.1021/acschemneuro.4c0079110.1021/acschemneuro.4c00791","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00791https://doi.org/10.1021/acschemneuro.4c00791","url":null,"abstract":"&lt;p &gt;Abnormal protein aggregation and associated neuronal-glial cell cytotoxicity lead to a plethora of neurodegenerative disorders. Most of the earlier investigations on understanding neurodegenerative disease progression and cure focused on neuronal damage and restoration potential. With increased evidence on the role of glial cells like microglia and astrocytes in mediating these disorders, more studies are dedicated to understanding the role of inflammatory responses mediated by glial cells and how they lead to neuroinflammation. Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder caused by TDP-43 aggregation that affects motor neurons. Pro-inflammatory microglia are considered to aggravate the disorder condition. In the current study, a previously reported molecule with TDP-43 inhibition, 3,3′-(acridine-4,5-diylbis(methylene))bis(1-(carboxymethyl)imidazol-3-ium) dibromide salt (&lt;b&gt;AIM4&lt;/b&gt;), is analyzed for its microglia polarization properties along with two other derivatives, 3,3′-(acridine-4,5-diylbis(methylene))bis(1-(2-ethoxy-2-oxoethyl)benzimidazol-3-ium) dibromide salt (&lt;b&gt;ABE&lt;/b&gt;) and 3,3′-(acridine-4,5-diylbis(methylene))bis(1-(carboxymethyl)benzoimidazol-3-ium) dibromide salt (&lt;b&gt;ABA&lt;/b&gt;). The 3,3′-(acridine-4,5-diylbis(methylene))bis(1-(2-ethoxy-2-oxoethyl)benzimidazol-3-ium) dibromide salt (&lt;b&gt;ABE&lt;/b&gt;) and 3,3′-(acridine-4,5-diylbis(methylene))bis(1-(carboxymethyl) benzimidazol-3-ium) dibromide salt (&lt;b&gt;ABA&lt;/b&gt;) display the increased ability to maintain microglial cells to anti-inflammatory state and TDP-43 binding as compared to 3,3′-(acridine-4,5-diylbis(methylene)) bis(carboxymethyl)imidazolium dibromide salt (&lt;b&gt;AIM4&lt;/b&gt;). This was confirmed from total nitrite levels, mitochondria membrane potential analysis, and molecular docking studies. The selected pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) displayed decreased levels, and anti-inflammatory cytokines IL-4 and IL-10 displayed increased levels, however not very significantly, upon treatment with all acridine derivatives. The compounds were investigated on lipopolysaccharides (LPS)-triggered mouse microglial cells and &lt;i&gt;Danio rerio&lt;/i&gt; embryos displaying no significant cytotoxicity and physiological changes (cardiac rhythm), respectively. In molecular docking studies, alanine at 315 mutated to glutamate of TDP-43 directly interacts with &lt;b&gt;AIM4&lt;/b&gt;. However, π–σ interactions of the aromatic backbone of acridine in &lt;b&gt;ABE&lt;/b&gt; and &lt;b&gt;ABA&lt;/b&gt; with 313 phenylalanine of TDP-43 along with hydrogen bonds formed between 309, 310 glycine amino acids and imidazolium bromide side chains rendered a stronger binding of these acridine derivatives with the protein potentially inhibiting fibrillation. &lt;b&gt;Conclusion: ABA&lt;/b&gt;, &lt;b&gt;ABE&lt;/b&gt;, and &lt;b&gt;AIM4&lt;/b&gt; maintain microglia in an anti-inflammatory state. However, more studies are required to understand its interaction with TDP-43 and the mechanism of its anti-inflammatory nat","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 6","pages":"1103–1116 1103–1116"},"PeriodicalIF":4.1,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143641208","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SCN8A Epileptic Encephalopathy Mutation Displays a Loss-of-Function Phenotype and Distinct Insensitivity to Valproate","authors":"Yudan Zhu,&nbsp;Guangfei Wang,&nbsp;Kaixuan Wang,&nbsp;Meng Sun,&nbsp;Lu Zhao,&nbsp;Yunqing Zeng,&nbsp;Cuina Yan,&nbsp;Yonghua Ji,&nbsp;Yangbo Hou*,&nbsp;Zhiping Li* and Jie Tao*,&nbsp;","doi":"10.1021/acschemneuro.4c0082810.1021/acschemneuro.4c00828","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00828https://doi.org/10.1021/acschemneuro.4c00828","url":null,"abstract":"<p >Voltage-gated sodium channels are the main targets of antiepileptic drugs, such as sodium valproate (VPA). Single nucleotide polymorphisms (SNPs) in the Nav1.6 isoform (<i>SCN8A</i>) have been reported to be closely associated with motor dysfunction in pediatric akathisia epileptica. In this study, we conducted a genetic screening of pediatric patients with seizures treated solely with VPA and identified two novel missense mutations of <i>SCN8A</i> (A1534V and Q1853H). Electrophysiological results revealed that the peak currents of the A1534V variant were smaller compared to that of the wild-type (WT) channel. The A1534V variant also caused a positive shift in the <i>I</i>–<i>V</i> curve, indicating a change in the voltage dependence of activation compared to the WT channels. In contrast, VPA induced a significant negative shift in the inactivation of both WT and A1534V mutant. However, the inhibition of currents by VPA was weaker in the A1534V variant than in WT. Furthermore, the recovery time constant of the A1534V variant was shorter than that of WT when treated with VPA. Regrettably, although the Q1853H variant can be expressed in HEK293T cells, the detected current is too small (approximately 50 pA). In conclusion, our results suggest that the A1534V mutation is a novel loss-of-function variant that exhibits moderate insensitivity to VPA. These results underscore the importance of Nav1.6 as a key target in epilepsy and highlight the necessity of analyzing its role in the pathological process.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 6","pages":"1132–1143 1132–1143"},"PeriodicalIF":4.1,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143641655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding the Nectin Interactome: Implications for Brain Development, Plasticity, and Neurological Disorders","authors":"Shreyash Santosh Yadav,&nbsp;Krishnamoorthy Srinivasan,&nbsp;Shyam Sunder Sharma and Ashok Kumar Datusalia*,&nbsp;","doi":"10.1021/acschemneuro.5c0006910.1021/acschemneuro.5c00069","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00069https://doi.org/10.1021/acschemneuro.5c00069","url":null,"abstract":"<p >The nectin family of cell adhesion molecules (CAMs) comprising nectins and nectin-like molecules has emerged as a key regulator of various pivotal neural processes, including neuronal development, migration, synapse formation, and plasticity. Nectins engage in homophilic and heterophilic interactions to mediate cell–cell adhesion, contributing to the establishment and maintenance of neural circuits. Their extracellular domains facilitate trans-synaptic interactions, while intracellular domains participate in signaling cascades influencing cytoskeletal dynamics and synaptic function. The exhibition of distinct localization patterns in neurons, astrocytes, and the blood–brain barrier underscores their diverse roles in the brain. The dysregulation of nectins has been implicated in several neurological disorders, such as neurodevelopmental disorders, depression, schizophrenia, and Alzheimer’s disease. This review examines the structural and functional characteristics of nectins and their distribution and molecular mechanisms governing neural connectivity and cognition. It further discusses experimental studies unraveling nectin-mediated pathophysiology and potential therapeutic interventions targeting nectin-related pathways. Collectively, this comprehensive analysis highlights the significance of nectins in brain development, function, and disorders, paving the way for future research directions and clinical implications.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 6","pages":"1000–1020 1000–1020"},"PeriodicalIF":4.1,"publicationDate":"2025-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143641654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential Effects of Aβ Peptides on the Plasmin-Dependent Degradation of ApoE3 and ApoE4","authors":"Merc M. Kemeh,&nbsp;Anthony J. Furnelli and Noel D. Lazo*,&nbsp;","doi":"10.1021/acschemneuro.5c0006510.1021/acschemneuro.5c00065","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00065https://doi.org/10.1021/acschemneuro.5c00065","url":null,"abstract":"<p >The <i>ApoE4</i> allele of apolipoprotein E (ApoE4) is the strongest hereditary predisposition to Alzheimer’s disease, even though ApoE4 only differs from the more common ApoE3 by a single amino acid substitution. Previous studies have shown that ApoE4 is more susceptible to proteolytic degradation than ApoE3. This is an important finding because of ApoE’s role in cholesterol homeostasis and lipid transport in the brain. The molecular determinants of the increased susceptibility of ApoE4 to proteolysis are unknown. Here, we apply a combination of spectrometric and spectroscopic methods to show that amyloid-β (Aβ) peptides, including Aβ(1–40) and Aβ(pyroE3–42), differentially modulate the plasmin-dependent degradation of ApoE3 and ApoE4. In particular, our data reveal that while the Aβ peptides do not affect the proteolysis of ApoE3, the peptides enhance the degradation of ApoE4 significantly. Overall, this work motivates therapeutic development that targets the Aβ-induced dysregulation of ApoE4 homeostasis in individuals carrying the <i>ApoE4</i> allele.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 6","pages":"1227–1237 1227–1237"},"PeriodicalIF":4.1,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143641200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Procognitive Potential of Neuroprotective Triazine 5-HT6 Receptor Antagonists Tested on Chronic Activity In Vivo in Rats: Computer-Aided Insight into the Role of Chalcogen-Differences on the Pharmacological Profile","authors":"Magdalena Jastrzębska-Więsek,&nbsp;Sabrina Garbo,&nbsp;Agnieszka Cios,&nbsp;Natalia Wilczyńska-Zawal,&nbsp;Anna Partyka,&nbsp;Ewelina Honkisz-Orzechowska,&nbsp;Ewa Żesławska,&nbsp;Jarosław Handzlik,&nbsp;Barbara Mordyl,&nbsp;Monika Głuch-Lutwin,&nbsp;Alessia Raucci,&nbsp;Marius Hittinger,&nbsp;Małgorzata Starek,&nbsp;Monika Dąbrowska,&nbsp;Wojciech Nitek,&nbsp;Tadeusz Karcz,&nbsp;Alicja Skórkowska,&nbsp;Joanna Gdula-Argasińska,&nbsp;Kinga Czarnota-Łydka,&nbsp;Patryk Pyka,&nbsp;Ewa Szymańska,&nbsp;Katarzyna Kucwaj-Brysz,&nbsp;Clemens Zwergel,&nbsp;Anna Wesołowska,&nbsp;Cecilia Battistelli* and Jadwiga Handzlik*,&nbsp;","doi":"10.1021/acschemneuro.4c0087310.1021/acschemneuro.4c00873","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00873https://doi.org/10.1021/acschemneuro.4c00873","url":null,"abstract":"<p >Among serotonin receptors, the 5-HT₆ subtype is an important protein target and its ligands may play a key role in the innovative treatment of cognitive disorders. This study aimed to extend the body of preclinical research on two naphthyl-derived methylpiperazine-1,3,5-triazine analogues with thioether (<b>WA-22</b>) or Se-ether (<b>PPK-32</b>) linkers, the newly described compounds having high affinity and selectivity for 5-HT₆ receptors and drug-like parameters in vitro. Thus, crystallography-supported deeper insight into their chemical properties, the comparison of their neuroprotective and pharmacokinetic profiles, and especially their impact on memory disturbances after chronic administration to rats were investigated. As a result, the chronic administration of <b>WA-22</b> completely reversed <b>(+)MK-801</b>-induced memory disturbances evaluated in the novel object recognition test (NORT) in rats. The pharmacokinetic and biochemical results support the notion that this 1,3,5-triazine 5-HT₆ receptor ligand could offer a promising therapeutic tool in CNS-related disorders. The selenium compound <b>PPK-32</b>, with a similar range of activity at acute administration, has shown even broader neuroprotective profiles, especially at the genetic level. However, for therapeutic use, its weaker pharmacokinetics (stability), which is a probable limit for action upon chronic administration, would require improvement, e.g., by an appropriate formulation.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 6","pages":"1190–1209 1190–1209"},"PeriodicalIF":4.1,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acschemneuro.4c00873","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143641202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulation of α-Synuclein Fibrillation and Toxicity by 4-Phenylbutyric Acid","authors":"Kristos Baffour,&nbsp;Neelima Koti,&nbsp;Tony Nyabayo,&nbsp;Sathvika Balerao,&nbsp;Carissa Sutton,&nbsp;David Johnson,&nbsp;Rishi Patel,&nbsp;Santimukul Santra and Tuhina Banerjee*,&nbsp;","doi":"10.1021/acschemneuro.4c0070910.1021/acschemneuro.4c00709","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00709https://doi.org/10.1021/acschemneuro.4c00709","url":null,"abstract":"<p >The protein misfolding and aggregation of α-synuclein (α-Syn) into neurotoxic amyloids underlies the pathogenesis of neurodegenerative diseases such as Parkinson’s disease (PD). Emerging evidence suggests that 4-phenylbutyrate (PBA) may play a role as a potential chemical chaperone for targeting α-Syn aggregation, but its molecular mechanism remains largely unknown. Using in vitro assays, we demonstrate that PBA treatment alters the pattern of α-Syn aggregation, as evidenced by reduced formation of oligomeric species and its increased susceptibility to proteolytic cleavage under the influence of PBA. Proteinase K (PK) assays, surface plasmon resonance (SPR), Nile red assays, and cytotoxicity assays indicate that PBA interacts with the extensive hydrophobic contacts of α-Syn oligomers and significantly reduces α-Syn-amyloid-induced toxicity. Furthermore, using thioflavin T-based assays, we elucidated the kinetics of PBA-mediated modulation of α-Syn aggregation, highlighting its role in accelerating the formation of α-Syn amyloid fibrils. Molecular dynamics (MD) simulations suggest PBA’s role in the destabilization of the C-terminus in α-Syn oligomers through multiple residue interactions. Collectively, our findings provide compelling evidence for the neuroprotective potential of PBA in targeting protein misfolding and aggregation in PD and suggest an avenue for disease-modifying interventions in neurodegenerative disorders.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 6","pages":"1066–1078 1066–1078"},"PeriodicalIF":4.1,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acschemneuro.4c00709","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143641204","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of SSR504734, a Selective Glycine Transporter Type 1 Inhibitor, on Seizure Thresholds, Neurotransmitter Levels, and Inflammatory Markers in Mice","authors":"Nikola Gapińska,&nbsp;Piotr Wlaź,&nbsp;Elżbieta Wyska,&nbsp;Artur Świerczek,&nbsp;Krzysztof Kamiński,&nbsp;Marcin Jakubiec,&nbsp;Michał Abram,&nbsp;Katarzyna Ciepiela,&nbsp;Gniewomir Latacz,&nbsp;Tymoteusz Słowik,&nbsp;Dawid Krokowski,&nbsp;Łukasz Jarosz,&nbsp;Artur Ciszewski and Katarzyna Socała*,&nbsp;","doi":"10.1021/acschemneuro.5c0003910.1021/acschemneuro.5c00039","DOIUrl":"https://doi.org/10.1021/acschemneuro.5c00039https://doi.org/10.1021/acschemneuro.5c00039","url":null,"abstract":"<p >Studies have revealed that inhibition of glycine transporter type 1 (GlyT1) may provide a balanced regulation between excitation and inhibition in some brain structures and, thereby, modulate seizure activity. Data on the role of GlyT1 in epilepsy are, however, very limited. Here, we examined the effect of SSR504734, a highly selective and reversible GlyT1 inhibitor, on three acute seizure tests in mice. We also evaluated its impact on neurotransmitter levels in the relevant brain structures following seizures, possible adverse effects, and changes in the levels of inflammatory mediators in the serum and liver. In addition, in vivo pharmacokinetic profile and in vitro ADME-Tox properties of SSR504734 were investigated. The results show that SSR504734 significantly increased the threshold for tonic hindlimb extension in the MEST test after acute and repeated treatment but had no influence on seizure thresholds in the 6 Hz and i.v. PTZ seizure tests. SSR504734 did not affect the levels of glutamate, GABA, glycine, or adenosine in brain structures of mice with MES-induced seizures. However, after acute treatment, the concentration of glutamate and adenosine in the brainstem of control animals (i.e., without seizures) decreased. Moreover, SSR504734 increased the levels of inflammatory markers (TNF-α, Il-1β, IL-6, IL-10, and TLR4) in serum. In vivo pharmacokinetic profiling and in vitro ADME-Tox data confirmed suitable drug-like properties of SSR504734, including its notable penetration into brain tissue. However, possible hepatotoxicity at higher doses should be taken into account. Further studies should be considered to better characterize the SSR504734-mediated effects as well as to validate GlyT1 as a potential new molecular target in epilepsy treatment.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 6","pages":"1210–1226 1210–1226"},"PeriodicalIF":4.1,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acschemneuro.5c00039","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143641157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of the Parkinson’s Disease-Related Protein DJ-1 by Endogenous Neurotoxins of the 1,2,3,4-Tetrahydroisoquinoline Family","authors":"Catherine Laurent,&nbsp;Gabrielle Poncet,&nbsp;Tristan Herskovits,&nbsp;Rodolphe Alves de Sousa,&nbsp;Laurent Le Corre,&nbsp;Mohammed Al-Azzani,&nbsp;Annekatrin Koenig,&nbsp;Serge Birman,&nbsp;Tiago Fleming Outeiro,&nbsp;Daniel Mansuy and Julien Dairou*,&nbsp;","doi":"10.1021/acschemneuro.4c0055910.1021/acschemneuro.4c00559","DOIUrl":"https://doi.org/10.1021/acschemneuro.4c00559https://doi.org/10.1021/acschemneuro.4c00559","url":null,"abstract":"<p >The protein DJ-1 appears to play a protective role in the development of Parkinson’s disease (PD). Here, we show that endogenous neurotoxins of the 1,2,3,4-tetrahydroisoquinoline family (TIQs), formed upon reaction of various aldehydes such as methylglyoxal (MGO) with the neurotransmitter dopamine, act as irreversible inhibitors of the esterase activity of human DJ-1, with IC50 values between 15 and 57 μM. The presence of a catechol function appears to be essential for these inhibitory effects, which may be at the origin of the oxidation of cysteine 106, a crucial residue in the DJ-1 active site, thereby leading to DJ-1 inhibition. We also show that these endogenous neurotoxins inhibit the protective effects of DJ-1 against glycated guanosine diphosphate (GDP) formation and against alpha-synuclein (aSyn) aggregation induced by MGO. In total, the observed inhibition of DJ-1 by these endogenous neurotoxins may contribute to their damaging effects on the nervous system and, should be taken into account in therapeutic strategies for PD and related disorders.</p>","PeriodicalId":13,"journal":{"name":"ACS Chemical Neuroscience","volume":"16 6","pages":"1034–1042 1034–1042"},"PeriodicalIF":4.1,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143641170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}