Neuroprotective and Nootropic Actions of a Novel Cyclized Dipeptide after Controlled Cortical Impact Injury in Mice

Faden, Alan I.; Fox, Gerard B.; Di, Xiao; Knoblach, Susan M.; Černak, Ibolja; Mullins, Paul G.; Nikolaeva, Maria; Kozikowski, Alan P.

doi:10.1097/01.wcb.0000046144.31247.33

Cited by 35 publications

(36 citation statements)

References 33 publications

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“…Many of these compounds exhibit useful biological properties, such as antibacterial (e.g., bicyclomycin), immunosuppressive (e.g., gliotoxin), and antitumoral (e.g., verticillin) activity, and have been noted in all kinds of organisms, including Streptomyces spp. and bacilli, as well as animals and humans (14,16,22). DKPs can be formed after proteolytic digestion of precursor molecules or synthesized from dedicated NRPS systems, as was shown for the biosynthetic clusters for ergotamine (36) and albonoursin (22).…”

Section: Discussionmentioning

confidence: 99%

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In Vivo Production of Artificial Nonribosomal Peptide Products in the Heterologous Host Escherichia coli

Gruenewald

Mootz

Stehmeier

et al. 2004

Appl Environ Microbiol

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Nonribosomal peptide synthetases represent the enzymatic assembly lines for the biosynthesis of pharmacologically relevant natural peptides, e.g., cyclosporine, vancomycin, and penicillin. Due to their modular organization, in which every module accounts for the incorporation of a single amino acid, artificial assembly lines for the production of novel peptides can be constructed by biocombinatorial approaches. Once transferred into an appropriate host, these hybrid synthetases could facilitate the bioproduction of basically any peptide-based molecule. In the present study, we describe the fermentative production of the cyclic dipeptide D-Phe-Pro-diketopiperazine, as a prototype for the exploitation of the heterologous host Escherichia coli, and the use of artificial nonribosomal peptide synthetases. E. coli provides a tremendous potential for genetic engineering and was manipulated in our study by stable chromosomal integration of the 4-phosphopantetheine transferase gene sfp to ensure heterologous production of fully active holoenzmyes. D-Phe-Pro-diketopiperazine is formed by the TycA/TycB1 system, whose components represent the first two modules for tyrocidine biosynthesis in Bacillus brevis. Coexpression of the corresponding genes in E. coli gave rise to the production of the expected diketopiperazine product, demonstrating the functional interaction of both modules in the heterologous environment. Furthermore, the cyclic dipeptide is stable and not toxic to E. coli and is secreted into the culture medium without the need for any additional factors. Parameters affecting the productivity were comprehensively investigated, including various genetic setups, as well as variation of medium composition and temperature. By these means, the overall productivity of the artificial system could be enhanced by over 400% to yield about 9 mg of D-Phe-Pro-diketopiperazine/liter. As a general tool, this approach could allow the sustainable bioproduction of peptides, e.g., those used as pharmaceuticals or fine chemicals.

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Section: Discussionmentioning

confidence: 99%

“…This dipeptide is autocatalytically released to give the cyclic D-PhePro-diketopiperazine (D-Phe-Pro-DKP) (42). DKPs constitute a class of natural products with interesting biological properties (14,16,22).…”

mentioning

confidence: 99%

In Vivo Production of Artificial Nonribosomal Peptide Products in the Heterologous Host Escherichia coli

Gruenewald

Mootz

Stehmeier

et al. 2004

Appl Environ Microbiol

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“…9,20,21 The device consists of a narrow wooden beam 5 mm wide and 120 cm in length, which is suspended 1 m above the ground. The mouse was placed on the beam and the number of footfaults for the right hindlimb was recorded over 50 steps.…”

Section: Motor Function Evaluationmentioning

confidence: 99%

“…It results in consistent histological damage and sustained behavioral deficits. [6][7][8][9] CCI can cause intracerebral hemorrhage, cytotoxic and vasogenic brain edema, neuronal loss, and motor and cognitive deficits. [10][11][12][13][14][15][16] Both behavioral and histological outcomes are injury-severity dependent, as demonstrated by varying impact depth and/or velocity in rats, 17,18 or mice.…”

Section: Introductionmentioning

confidence: 99%

Comparing the Predictive Value of Multiple Cognitive, Affective, and Motor Tasks after Rodent Traumatic Brain Injury

Zhao

Loane

Murray

et al. 2012

Journal of Neurotrauma

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140

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Controlled cortical impact injury (CCI) is a widely-used, clinically-relevant model of traumatic brain injury (TBI). Although functional outcomes have been used for years in this model, little work has been done to compare the predictive value of various cognitive and sensorimotor assessment tests, singly or in combination. Such information would be particularly useful for assessing mechanisms of injury or therapeutic interventions. Following isoflurane anesthesia, C57BL/6 mice were subjected to sham, mild (5.0 m/sec), moderate (6.0 m/sec), or severe (7.5 m/sec) CCI. A battery of behavioral tests were evaluated and compared, including the standard Morris water maze (sMWM), reversal Morris water maze (rMWM), novel object recognition (NOR), passive avoidance (PA), tail-suspension (TS), beam walk (BW), and open-field locomotor activity. The BW task, performed at post-injury days (PID) 0, 1, 3, 7, 14, 21, and 28, showed good discrimination as a function of injury severity. The sMWM and rMWM tests (PID 14-23), as well as NOR (PID 24 and 25), effectively discriminated spatial and novel object learning and memory across injury severity levels. Notably, the rMWM showed the greatest separation between mild and moderate/severe injury. PA (PID 27 and 28) and TS (PID 24) also reflected differences across injury levels, but to a lesser degree. We also compared individual functional measures with histological outcomes such as lesion volume and neuronal cell loss across anatomical regions. In addition, we created a novel composite behavioral score index from individual complementary behavioral scores, and it provided superior discrimination across injury severities compared to individual tests. In summary, this study demonstrates the feasibility of using a larger number of complementary functional outcome behavioral tests than those traditionally employed to follow post-traumatic recovery after TBI, and suggests that the composite score may be a helpful tool for screening new neuroprotective agents or for addressing injury mechanisms.

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“…128,129 35b is a cyclized dipeptide, somewhat related to a metabolic product of TRH, which blocks both apoptotic (caspase-dependent) and necrotic cell death in primary neuronal cell cultures, and shows striking neuroprotective actions following traumatic brain injury in rats and mice. 130,131 As molecular mechanisms of non-caspase-dependent programmed cell death are defined, other types of combined treatment or multipotential treatment approaches should be developed. Because multiple cell death pathways may have common upstream initiators, or share signal transduction cascades, new drug development strategies directed at such common targets should be considered for the treatment of both acute and chronic neurodegenerative disorders.…”

Section: Cell Death Mechanisms: Implications For Treatmentmentioning

confidence: 99%

Mechanisms of neural cell death: Implications for development of neuroprotective treatment strategies

2004

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Neuroprotective and Nootropic Actions of a Novel Cyclized Dipeptide after Controlled Cortical Impact Injury in Mice

Cited by 35 publications

References 33 publications

In Vivo Production of Artificial Nonribosomal Peptide Products in the Heterologous Host Escherichia coli

In Vivo Production of Artificial Nonribosomal Peptide Products in the Heterologous Host Escherichia coli

Comparing the Predictive Value of Multiple Cognitive, Affective, and Motor Tasks after Rodent Traumatic Brain Injury

Mechanisms of neural cell death: Implications for development of neuroprotective treatment strategies

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