Li⁺ based drugs have been used for the treatment of psychiatric disorders due to their mood stabilizing role for decades. Recently, several studies reported the protective effect of Li⁺ against severe neuropathologies such as Parkinson's, Alzheimer's, and Huntington's disease. Surprisingly, despite a broad range of Li⁺ effects on neurological conditions, little is known about its molecular mechanism. In this study, we propose that neuronal calcium sensor 1 (NCS1), can be an effective molecular target for Li⁺ action. Here we show that the EF-hands in ApoNCS1 have submillimolar affinity for Li⁺ with K_d = 223 ± 19 μM. Li⁺ binding to ApoNCS1 quenches Trp emission intensity, suggesting distinct Trp sidechains environment in Li⁺NCS1 compared to ApoNCS1 and Ca²⁺NCS1. Li⁺ association also stabilizes the protein α-helical structure, in a similar way to Ca²⁺. Li⁺ association does not promote NCS1 dimerization. Association of Li⁺ increases NCS1 affinity for the D2R receptor binding peptide, in a similar way to Ca²⁺, however, the affinity of NCS1 for chlorpromazine is reduced with respect to Ca²⁺NCS1, possibly due to a decrease in solvent exposed hydrophobic area on the NCS1 surface in the presence of Li⁺. MD simulation data suggests that Li⁺ ions are coordinated by four oxygens from Asp and Glu sidechains and one carbonyl oxygen, in a similar way as reported previously for Li⁺ binding to DREAM. Overall, the data shows that Li⁺ binds to EF-hands of NCS1 and Li⁺NCS1 interactions may be involved in the potential neuroprotective role of Li⁺ against psychotic disorders.

2023-05-01·Neuroscience & Biobehavioral Reviews

Lithium engages autophagy for neuroprotection and neuroplasticity: Translational evidence for therapy

Review

作者: Fornai, Francesco ; Lazzeri, Gloria ; Biagioni, Francesca ; Giorgi, Filippo S ; Puglisi-Allegra, Stefano ; Busceti, Carla L

Here an overview is provided on therapeutic/neuroprotective effects of Lithifum (Li⁺) in neurodegenerative and psychiatric disorders focusing on the conspicuous action of Li⁺ through autophagy. The effects on the autophagy machinery remain the key molecular mechanisms to explain the protective effects of Li⁺ for neurodegenerative diseases, offering potential therapeutic strategies for the treatment of neuropsychiatric disorders and emphasizes a crossroad linking autophagy, neurodegenerative disorders, and mood stabilization. Sensitization by psychostimulants points to several mechanisms involved in psychopathology, most also crucial in neurodegenerative disorders. Evidence shows the involvement of autophagy and metabotropic Glutamate receptors-5 (mGluR5) in neurodegeneration due to methamphetamine neurotoxicity as well as in neuroprotection, both in vitro and in vivo models. More recently, Li⁺ was shown to modulate autophagy through its action on mGluR5, thus pointing to an additional way of autophagy engagement by Li⁺ and to a substantial role of mGluR5 in neuroprotection related to neural e neuropsychiatry diseases. We propose Li⁺ engagement of autophagy through the canonical mechanisms of autophagy machinery and through the intermediary of mGluR5.

2022-01-01·Cellular and Molecular Neurobiology3区 · 医学

Lithium as a Neuroprotective Agent for Bipolar Disorder: An Overview

3区 · 医学

Review

作者: Ochoa, Enrique L M

Lithium (Li⁺) is a first option treatment for adult acute episodes of Bipolar Disorder (BD) and for the prophylaxis of new depressed or manic episodes. It is also the preferred choice as maintenance treatment. Numerous studies have shown morphological abnormalities in the brains of BD patients, suggesting that this highly heritable disorder may exhibit progressive and deleterious changes in brain structure. Since treatment with Li⁺ ameliorates these abnormalities, it has been postulated that Li⁺ is a neuroprotective agent in the same way atypical antipsychotics are neuroprotective in patients diagnosed with schizophrenia spectrum disorders. Li⁺'s neuroprotective properties are related to its modulation of nerve growth factors, inflammation, mitochondrial function, oxidative stress, and programmed cell death mechanisms such as autophagy and apoptosis. Notwithstanding, it is not known whether Li⁺-induced neuroprotection is related to the inhibition of its putative molecular targets in a BD episode: the enzymes inositol-monophosphatase, (IMPase), glycogen-synthase-kinase 3β (GSK3), and Protein kinase C (PKC). Furthermore, it is uncertain whether these neuroprotective mechanisms are correlated with Li⁺'s clinical efficacy in maintaining mood stability. It is expected that in a nearby future, precision medicine approaches will improve diagnosis and expand treatment options. This will certainly contribute to ameliorating the medical and economic burden created by this devastating mood disorder.

100 项与 LIF-316 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
不孕	临床1期	-	Enhance Biotech, Inc.	-
不孕	临床1期	美国	-	-

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


ESMO2023	N/A	局部晚期鳞状细胞癌新辅助	923	LI (+/- CIZ) + SOC	(衊鏇繭遞窪艱齋築鏇遞) = 獵蓋膚憲膚壓構築齋鏇積夢艱窪積淵衊繭鹽範 (鬱願糧觸憲觸淵築鹽齋 )	-	2023-10-22
				SOC only	(衊鏇繭遞窪艱齋築鏇遞) = 廠築積廠衊糧鑰鏇淵鏇積夢艱窪積淵衊繭鹽範 (鬱願糧觸憲觸淵築鹽齋 )