Amelioration of dementia induced by Aβ 22-35 through rectal delivery of undecapeptide-hEGF to mouse brain

• Published in: International journal of pharmaceutics Vol. 405; no. 1; pp. 1 - 8
• Main Authors: Zhao, Bao-Quan, Guo, Yan-Ru, Li, Xu-Ling, Zang, Ting, Qu, Heng-Yan, Zhou, Jian-Ping, Li, Qian, Sun, Man-Ji
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 28.02.2011; Elsevier
• Subjects: Administration, Rectal; Amyloid beta-Peptides - metabolism; animal experimentation; Animals; Aβ 22-35 peptide; Biological and medical sciences; Blood-brain barrier; Blood-Brain Barrier - metabolism; brain; Brain - metabolism; Cell Membrane Permeability - drug effects; Cell Proliferation - drug effects; Dementia; Dementia - drug therapy; Dementia - metabolism; epidermal growth factor; Epidermal Growth Factor - administration & dosage; Epidermal Growth Factor - genetics; Epidermal Growth Factor - pharmacokinetics; Epidermal Growth Factor - pharmacology; General pharmacology; Humans; intravenous injection; Learning Disorders - drug therapy; Medical sciences; Memory Disorders - drug therapy; Mice; mucosa; neurodegenerative diseases; Oligopeptides - administration & dosage; Oligopeptides - pharmacokinetics; Oligopeptides - pharmacology; P11-hEGF; permeability; permeates; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; polypeptides; proteins; Recombinant Fusion Proteins - administration & dosage; Recombinant Fusion Proteins - blood; Recombinant Fusion Proteins - pharmacokinetics; Recombinant Fusion Proteins - pharmacology; Rectal delivery; rectum; PTD; BBB; DAB; Amp; Aβ 22-35 peptide; Aβ 22-35; OmpA; hEGF; IV; P11-hEGF; GFAP; AUC; DMEM; P11; SDS-PAGE; Blood-brain barrier; FBS; IPTG; Rectal delivery; BrdU; ELISA; Dementia; Performance evaluation; Pharmaceutical technology; Rodentia; Route of administration; Blood brain barrier; Rectal administration; Encephalon; Vertebrata; Mammalia; Mouse; Animal; Rectum; Degenerative disease; Technique; Pharmacokinetics
• DOI: 10.1016/j.ijpharm.2010.11.018
• ISSN: 0378-5173

Distribution of P11-hEGF and hEGF after IV injection or per rectum in mice ( n = 6). P11-hEGF or hEGF (normalized to 40 μg hEGF) were IV injected to the mice. The animals were killed at various time intervals after injection, and the organs (brain, heart, liver, spleen, lung, kidney and stomach) were immediately removed. Tissue homogenates (1:10, w/v) were prepared and stored at −20 °C. The contents of EGF in various tissue homogenates were quantitatively determined by the radio-immunological method. (A and C) P 11-hEGF; (B and D) hEGF (Sigma). A group of growth factors have been shown to play important roles in amelioration of the malfunction of the neurodegenerative diseases. However, the proteins or polypeptides passing across the blood-brain barrier (BBB) to access the brain parenchyma are relatively few so that it hinders the therapies in clinic. Here a genetically reconstructed fusion peptide of human epidermal growth factor (hEGF) with an undecapeptide YGRKKRRQRRR (P11) was used to investigate the permeability between the cell membrane and the BBB via rectal administration. The efficiency to rescue the Aβ 22-35-induced dementia in mice was assessed after administration of P11-hEGF per rectal. Our results showed that P11-hEGF permeates across not only the 3T3 cell membrane in vitro, but also the endothelia of vessels after intravenous injection (IV), and the mucosa of the rectum after per rectal administration. Further results showed that the circulating P11-hEGF allowed penetrating through the blood-brain barrier and then getting into the brain manifesting biological responses. In the animal experiments, treatment with P11-hEGF not only ameliorated the dementia induced by Aβ 22-35 but also rescued the dementia of the aged mice, no matter how it was administrated (IV or per rectal). These results suggest that the rectal non-invasive delivery of the P11 polypeptide-conjugated growth factor is an efficient way for BBB transduction, thus raises the hope of real therapeutic progress against neurodegenerative diseases.