Therapeutic Effect of Novel Cyanopyrrolidine-Based Prolyl Oligopeptidase Inhibitors in Rat Models of Amnesia

Prolyl oligopeptidase (POP) is a large cytosolic serine peptidase that is altered in patients with Alzheimer’s disease, Parkinsonian syndrome, muscular dystrophies, and other denervating diseases. Thus, POP may represent a relevant therapeutic target for treatment of neuropsychiatric disorders and neurodegenerative diseases. Here, we report the characterization of five novel cyanopyrrolidine-based compounds (BocTrpPrdN, BocGlyPrdN, CbzMetPrdN, CbzGlnPrdN, and CbzAlaPrdN) and show that they are potent inhibitors of POP and are predicted to penetrate the blood-brain barrier (BBB). Indeed, we show that CbzMetPrdN penetrates the rat BBB and effectively inhibits POP in the brain when administered intraperitoneally. Furthermore, molecular modeling confirmed these compounds likely inhibit POP via interaction with the POP catalytic site. We evaluated protective effects of the cyanopyrrolidine-based POP inhibitors using scopolamine- and maximal electroshock-induced models of amnesia in rats and showed that BocTrpPrdN, BocGlyPrdN, CbzMetPrdN, and CbzGlnPrdN significantly prolonged conditioned passive avoidance reflex (CPAR) retention time when administered intraperitoneally (1 and 2 mg/kg) before evaluation in both models of amnesia, although CbzAlaPrdN was not effective in scopolamine-induced amnesia. Our data support previous reports on the antiamnesic effects of prolinal-based POP inhibitors and indicate an important role of POP in the regulation of learning and memory processes in the CNS.

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Characterization of Simian Immunodeficiency Virus (SIV) That Induces SIV Encephalitis in Rhesus Macaques with High Frequency: Role of TRIM5 and Major Histocompatibility Complex Genotypes and Early Entry to the Brain

Journal of Virology ◽

10.1128/jvi.01996-14 ◽

2014 ◽

Vol 88 (22) ◽

pp. 13201-13211 ◽

Cited By ~ 15

Author(s):

K. Matsuda ◽

Q. Dang ◽

C. R. Brown ◽

B. F. Keele ◽

F. Wu ◽

...

Keyword(s):

Major Histocompatibility Complex ◽

Simian Immunodeficiency Virus ◽

High Frequency ◽

Rhesus Macaques ◽

Early Entry ◽

Histocompatibility Complex ◽

Immunodeficiency Virus ◽

The Brain

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A Review on the Effects of Melatonin on Fetal Protection during Pregnancy with Intrauterine Inflammation

JOURNAL OF THE KOREAN SOCIETY OF MATERNAL AND CHILD HEALTH ◽

10.21896/jksmch.2020.24.4.196 ◽

2020 ◽

Vol 24 (4) ◽

pp. 196-203

Author(s):

Jang Mee Kim ◽

Ji Yeon Lee

Keyword(s):

Oxidative Stress ◽

Pregnant Women ◽

Animal Studies ◽

Protective Effects ◽

Fetal Protection ◽

Inflammatory Drugs ◽

Anti Inflammatory ◽

The Brain ◽

Fetal Inflammatory Response

Intrauterine inflammation is defined as the inflammation of the chorion, amnion, and placenta. Untreated inflammation increases the risk of fetal inflammatory response syndrome, which may result in multiorgan diseases involving the brain, cardiovascular system, lung, eye, and intestine. Therefore, controlling inflammation is critical in pregnant women to reduce the risk of diseases. However, there are no safe and effective anti-inflammatory drugs for administration during pregnancy. Although the primary function of melatonin is to control circadian rhythms, it has protective effects against cellular insults occurring from hypoxia, oxidative stress, and inflammation. While animal studies support the effective and safe role of melatonin in improving pregnancy-related morbidities, it leaves plenty of opportunities for clinical studies investigating its anti-inflammatory, antioxidant, and protective effects against insults induced by intrauterine inflammation. Therefore, it will be worthwhile to investigate antenatal supplementation of melatonin in pregnant women with intrauterine inflammation to reduce the incidence of associated comorbidities.

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Role of DHA metabolites in protective effects of DHA supplementation in the brains of rotenone-induced rat models of Parkinson’s disease

10.3390/iecbm2020-08583 ◽

2020 ◽

Author(s):

Ami Oguro ◽

Yasuhiro Ishihara

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Protective Effects ◽

Rat Models

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Functional Characterization of Colon-Cancer-Associated Variants in ADAM17 Affecting the Catalytic Domain

Biomedicines ◽

10.3390/biomedicines8110463 ◽

2020 ◽

Vol 8 (11) ◽

pp. 463

Author(s):

Jan Philipp Dobert ◽

Anne-Sophie Cabron ◽

Philipp Arnold ◽

Egor Pavlenko ◽

Stefan Rose-John ◽

...

Keyword(s):

Catalytic Domain ◽

Functional Characterization ◽

Tumor Development ◽

Point Mutations ◽

Modern World ◽

Protective Effects ◽

Tissue Samples ◽

Membrane Bound

Although extensively investigated, cancer is still one of the most devastating and lethal diseases in the modern world. Among different types, colorectal cancer (CRC) is most prevalent and mortal, making it an important subject of research. The metalloprotease ADAM17 has been implicated in the development of CRC due to its involvement in signaling pathways related to inflammation and cell proliferation. ADAM17 is capable of releasing membrane-bound proteins from the cell surface in a process called shedding. A deficiency of ADAM17 activity has been previously shown to have protective effects against CRC in mice, while an upregulation of ADAM17 activity is suspected to facilitate tumor development. In this study, we characterize ADAM17 variants found in tissue samples of cancer patients in overexpression studies. We here focus on point mutations identified within the catalytic domain of ADAM17 and could show a functional dysregulation of the CRC-associated variants. Since the catalytic domain of ADAM17 is the only region structurally determined by crystallography, we study the effect of each point mutation not only to learn more about the role of ADAM17 in cancer, but also to investigate the structure–function relationships of the metalloprotease.

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Characterization of two myostatin genes in pufferfish Takifugu bimaculatus: sequence, genomic structure, and expression

PeerJ ◽

10.7717/peerj.9655 ◽

2020 ◽

Vol 8 ◽

pp. e9655

Author(s):

Yinzhen Sheng ◽

Yulong Sun ◽

Xin Zhang ◽

Haifu Wan ◽

Chengjie Yao ◽

...

Keyword(s):

Skeletal Muscle ◽

Genomic Structure ◽

Muscle Growth ◽

Negative Regulator ◽

Pigment Formation ◽

Formation Stage ◽

Proliferation And Differentiation ◽

The Brain

Myostatin (MSTN) is a negative regulator of muscle growth, which restrains the proliferation and differentiation of myoblasts. To understand the role of two mstn genes of Takifugu bimaculatus, the full-length cDNAs of 1131 bp Tbmstn1 and 1,080 bp Tbmstn2 were obtained from the T. bimaculatus’ genomic database, which encodes 376 and 359 amino acids, respectively. The results of qRT-PCR showed that Tbmstn1 was expressed in the eye, kidney, spleen, skeletal muscle, gill, and brain, and the expression level in the skeletal muscle was extremely significantly higher than in other examined tissues. Tbmstn2 was expressed in the skin, skeletal muscle, gill, and brain, and had the highest expression in the skeletal muscle, followed by expression in the brain. Meanwhile, in different stages of embryonic development, the expression of Tbmstn1 started from the gastrula stage. Its expression in the eye-pigment formation stage and hatching stage was significantly higher than that in other stages. The Tbmstn2 was expressed in all examined embryonic stages with different levels, and the highest expression was detected in the eye-pigment formation stage. These results suggested that Tbmstn1 and Tbmstn2 may involve in the development of skeletal muscle, and Tbmstn2 may be related to the formation of nervous system.

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Antigenic and genetic characterization of a divergent African virus, Ikoma lyssavirus

Journal of General Virology ◽

10.1099/vir.0.061952-0 ◽

2014 ◽

Vol 95 (5) ◽

pp. 1025-1032 ◽

Cited By ~ 29

Author(s):

Daniel L. Horton ◽

Ashley C. Banyard ◽

Denise A. Marston ◽

Emma Wise ◽

David Selden ◽

...

Keyword(s):

Laboratory Mouse ◽

Rabies Vaccine ◽

Molecular Techniques ◽

Phenotypic Characteristics ◽

Nucleotide Divergence ◽

The Brain

In 2009, a novel lyssavirus (subsequently named Ikoma lyssavirus, IKOV) was detected in the brain of an African civet (Civettictis civetta) with clinical rabies in the Serengeti National Park of Tanzania. The degree of nucleotide divergence between the genome of IKOV and those of other lyssaviruses predicted antigenic distinction from, and lack of protection provided by, available rabies vaccines. In addition, the index case was considered likely to be an incidental spillover event, and therefore the true reservoir of IKOV remained to be identified. The advent of sensitive molecular techniques has led to a rapid increase in the discovery of novel viruses. Detecting viral sequence alone, however, only allows for prediction of phenotypic characteristics and not their measurement. In the present study we describe the in vitro and in vivo characterization of IKOV, demonstrating that it is (1) pathogenic by peripheral inoculation in an animal model, (2) antigenically distinct from current rabies vaccine strains and (3) poorly neutralized by sera from humans and animals immunized against rabies. In a laboratory mouse model, no protection was elicited by a licensed rabies vaccine. We also investigated the role of bats as reservoirs of IKOV. We found no evidence for infection among 483 individuals of at least 13 bat species sampled across sites in the Serengeti and Southern Kenya.

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Iron and Mechanisms of Neurotoxicity

International Journal of Alzheimer s Disease ◽

10.4061/2011/720658 ◽

2011 ◽

Vol 2011 ◽

pp. 1-9 ◽

Cited By ~ 20

Author(s):

Gabriela A. Salvador ◽

Romina M. Uranga ◽

Norma M. Giusto

Keyword(s):

Neurodegenerative Diseases ◽

Neurodegenerative Disorders ◽

Neuronal Dysfunction ◽

Protective Mechanisms ◽

Copper Zinc ◽

Final Response ◽

The Brain ◽

Oxidative Insult

The accumulation of transition metals (e.g., copper, zinc, and iron) and the dysregulation of their metabolism are a hallmark in the pathogenesis of several neurodegenerative diseases. This paper will be focused on the mechanism of neurotoxicity mediated by iron. This metal progressively accumulates in the brain both during normal aging and neurodegenerative processes. High iron concentrations in the brain have been consistently observed in Alzheimer's (AD) and Parkinson's (PD) diseases. In this connection, metalloneurobiology has become extremely important in establishing the role of iron in the onset and progression of neurodegenerative diseases. Neurons have developed several protective mechanisms against oxidative stress, among them, the activation of cellular signaling pathways. The final response will depend on the identity, intensity, and persistence of the oxidative insult. The characterization of the mechanisms mediating the effects of iron-induced increase in neuronal dysfunction and death is central to understanding the pathology of a number of neurodegenerative disorders.

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Immune Modulation as a Key Mechanism for the Protective Effects of Remote Ischemic Conditioning After Stroke

Frontiers in Neurology ◽

10.3389/fneur.2021.746486 ◽

2021 ◽

Vol 12 ◽

Author(s):

Sima Abbasi-Habashi ◽

Glen C. Jickling ◽

Ian R. Winship

Keyword(s):

Immune Modulation ◽

Ischemia Reperfusion ◽

Treatment Strategies ◽

Protective Effects ◽

Humoral Factors ◽

Remote Ischemic Conditioning ◽

Ischemic Conditioning ◽

Mediators Of Inflammation ◽

The Brain

Remote ischemic conditioning (RIC), which involves a series of short cycles of ischemia in an organ remote to the brain (typically the limbs), has been shown to protect the ischemic penumbra after stroke and reduce ischemia/reperfusion (IR) injury. Although the exact mechanism by which this protective signal is transferred from the remote site to the brain remains unclear, preclinical studies suggest that the mechanisms of RIC involve a combination of circulating humoral factors and neuronal signals. An improved understanding of these mechanisms will facilitate translation to more effective treatment strategies in clinical settings. In this review, we will discuss potential protective mechanisms in the brain and cerebral vasculature associated with RIC. We will discuss a putative role of the immune system and circulating mediators of inflammation in these protective processes, including the expression of pro-and anti-inflammatory genes in peripheral immune cells that may influence the outcome. We will also review the potential role of extracellular vesicles (EVs), biological vectors capable of delivering cell-specific cargo such as proteins and miRNAs to cells, in modulating the protective effects of RIC in the brain and vasculature.

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