Development of neuropeptide drugs that cross the blood-brain barrier

Egleton, Richard D.; Davis, Thomas P.

doi:10.1602/neurorx.2.1.44

Cited by 138 publications

(117 citation statements)

References 132 publications

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“…The D-peptide blocks anti-NR2 Ab binding and does not interfere with receptor function. D-peptides have compelling therapeutic attributes: they can be given orally because they are resistant to protease digestion; they have a half-life of Ϸ6 h; and they can be engineered to cross the BBB (13,(35)(36)(37). D-peptides may, therefore, be a potential therapeutic for many Ab-mediated conditions.…”

Section: Discussionmentioning

confidence: 99%

Immunity and behavior: Antibodies alter emotion

Huerta

Kowal

DeGiorgio

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

256

226

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Systemic lupus erythematosus is an autoimmune disease in which most patients express Abs that bind double-stranded DNA. Recent work has shown that a subset of lupus Abs can crossreact with the NR2A and NR2B subunits of the NMDA receptor. This receptor is expressed in neurons throughout the brain but is at highest density within cells of the hippocampus, amygdala, and hypothalamus. The neurons in the CNS are normally protected from brain-reactive Abs by the blood-brain barrier (BBB); however, a breach in the barrier's integrity exposes neurons to potentially pathogenic Abs. Previously, we have shown that mice that are immunized with a peptide mimetope of DNA produce lupus-like Abs that crossreact with DNA and the NMDA receptor. Moreover, after abrogation of the BBB by treatment with lipopolysaccharide, the immunized mice display hippocampal neuron damage with ensuing memory impairment. Given that rises in epinephrine can increase cerebral blood flow and can cause leaks in the BBB, we decided to investigate whether epinephrine could act as a permissive agent for Ab-mediated neurotoxicity. Here, we show that peptide-immunized mice, given epinephrine to open the BBB, lose neurons in the lateral amygdala and develop a behavioral disorder characterized by a deficient response to fear-conditioning paradigms. Thus, the agent used to open the BBB determines which brain region is made vulnerable to neurotoxic Abs, and Abs that penetrate brain tissue can cause changes not only in cognitive competence, but also in emotional behavior.amygdala ͉ anti-NMDA receptor antibody ͉ anti-DNA antibody ͉ fear conditioning ͉ systemic lupus erythematosus

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Section: Discussionmentioning

confidence: 99%

Immunity and behavior: Antibodies alter emotion

Huerta

Kowal

DeGiorgio

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

256

226

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“…α-Neo may have a lower intrinsic activity than other two peptides to cause receptor internalization and down-regulation although these three peptides show the similar level of intrinsic efficacy to stimulate GTPγS binding. In addition, α-Neo may be more susceptible than Dyn A and Dyn B to many endogenous proteases / peptidases present in serum in the incubation medium and / or associated with membranes (Egleton and Davis, 2005).…”

Section: Difference In Peptides-mediated Receptor Internalizationmentioning

confidence: 99%

“…Proteolytic enzymes in human serum are generally composed of endopeptidase, aminopeptidase, carboxypeptidase and angiotensin-converting enzyme (Checler, 1991;Van, V et al, 1999), which result in rapid clearance of peptides from circulation (Egleton and Davis, 2005). All of those enzymatic activities have been found in FBS (Glavas-Obrovac et al, 2005;Kozlowski et al, 1992).…”

Section: Stability Of Peptides In the Presence Of Serummentioning

confidence: 99%

Dynorphin peptides differentially regulate the human κ opioid receptor

Chen

Liu‐Chen

2007

Life Sciences

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Dynorphins, endogenous peptides for the κ opioid receptor, play important roles in many physiological and pathological functions. Here, we examined how prolonged treatment with three major prodynorphin peptides, dynorphin A (1-17) (Dyn A), dynorphin B (1-13) (Dyn B) and α-neoendorphin (α-Neo), regulated the human kappa opioid receptor (hKOR) stably expressed in Chinese hamster ovary (CHO) cells. Results from receptor binding and [ 35 S]GTPγS binding assays showed that these peptides were potent full agonists of the hKOR with comparable receptor reserve and intrinsic efficacy to stimulate G proteins. A 4-h incubation with α-Neo at a concentration of ∼600× EC 50 value (from [ 35 S]GTPγS binding) resulted in receptor down-regulation to a much lower extent than the incubation with Dyn A and Dyn B at comparable concentrations (∼10% vs. ∼65%). Extending incubation period and increasing concentrations did not significantly affect the difference. The plateau level of α-Neo-mediated receptor internalization (30 min) was significantly less than those of Dyn A and Dyn B. Omission of serum from the incubation medium or addition of peptidase inhibitors into the serum-containing medium enhanced α-Neo-, but not Dyn A-or Dyn B-, mediated receptor down-regulation and internalization; however, the degrees of α-Neo-induced adaptations were still significantly less than those of Dyn A and Dyn B. Thus, these endogenous peptides differentially regulate KOR after activating the receptor with similar receptor occupancy and intrinsic efficacy. Both stability in the presence of serum and intrinsic capacity to promote receptor adaptation play roles in the observed discrepancy among the dynorphin peptides.

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“…15 Although the natural compounds described above are known as pleiotropic antioxidants for their multiple medicinal benefits, they cannot cross the BBB when administered orally due to water insolubility and low bioavailability, a major stumbling block in CNS therapeutics, and are limited by their instability at physiological pH, rapid metabolism, and rapid systemic elimination. 31 Therefore, this has necessitated the development of an effective delivery system to provide an elevated pool of such antioxidants in the brain to protect neuronal cells against oxidative attack.…”

Section: Nanotechnology For Drug Delivery To the Brainmentioning

confidence: 99%

Therapeutic Potential of Natural Product-Based Oral Nanomedicines for Stroke Prevention

Mutoh

Taki

et al. 2016

Journal of Medicinal Food

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Cerebral stroke is the leading cause of death and permanent disability in elderly persons. The impaired glucose and oxygen transport to the brain during ischemia causes bioenergetic failure, leading to oxidative stress, inflammation, bloodbrain barrier dysfunction, and eventually cell death. However, the development of effective therapies against stroke has been hampered by insufficient oral absorption of pharmaceuticals and subsequent delivery to the brain. Nanotechnology has emerged as a new method of treating cerebral diseases, with the potential to fundamentally change currently available therapeutic approaches using compounds with low bioavailability. This perspective review provides an overview of the therapeutic potential of oral nanomedicines for stroke, focusing on novel natural product-loaded delivery system with potent antioxidant and anti-inflammatory effects.

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Development of neuropeptide drugs that cross the blood-brain barrier

Cited by 138 publications

References 132 publications

Immunity and behavior: Antibodies alter emotion

Immunity and behavior: Antibodies alter emotion

Dynorphin peptides differentially regulate the human κ opioid receptor

Therapeutic Potential of Natural Product-Based Oral Nanomedicines for Stroke Prevention

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