Neuroprotective peptide drug delivery and development: potential new therapeutics

doi:10.1016/S0166-2236(00)01931-7

Trends in Neurosciences

Volume 24, Issue 12, 1 December 2001, Pages 700-705

https://doi.org/10.1016/S0166-2236(00)01931-7 Get rights and content

Abstract

Alzheimer's disease and related neurodegenerative disorders are prevalent among the elderly and might be considered as the plague of the 21st century. It is thus imperative to find cures for these conditions. The use of nerve growth factor proteins as neuroprotective therapeutics is limited by their hindered mobility through the blood–brain barrier. Peptides provide an attractive alternative. However, do peptide derivatives retain the activity of the entire protein? Are they stable? Would peptides cross the blood–brain barrier and what are the potential side effects? Examples are put forth to strengthen our opinion that peptides are important candidates for future drug development.

Section snippets

Examples of peptides as drugs

Gonadotropin releasing hormone (GnRH; LH-RH) is used in the clinic (in a modified peptide form) as an anti-cancer and reproductive drug 3, 4. GnRH was one of the first neuropeptides to be recognized as a neurotransmitter ⁵, it can be applied by intranasal administration ⁶, and is able to cross the blood–brain barrier (BBB).

Vasopressin is another peptide used in the clinic ⁷. In addition to its antidiuretic effects ⁸, vasopressin has CNS effects, initially described in rats ⁹ where it modulates

Peptide drug delivery to the brain

An example for peptide delivery to the brain is the binding, transport and metabolism of phenylalanyl-3,4,5,-³H(N) arginine vasopressin (AVP) by the BBB (Ref. 18). Results indicate a time-dependent, progressive brain uptake in both homogenates and tissue depleted of cerebral microvessels. Intact [³H]AVP progressively declined during brain perfusion, from 49% at 1 min to 11.9% at 10 min ¹⁸. Furthermore, differential transport of rat and human interleukin-1alpha across the BBB was observed,

Active peptide fragments as neuroprotective agents, our work in the context of others

CNS drug design requires small, specific molecules with enhanced brain availability. Small, stabilized peptide fragments might represent attractive candidates. The shared peptide epitope of VIP with the envelope protein of the immunodeficiency virus (gp120) was suggested as a neuroprotective intranasally delivered drug [termed peptide T (33, 41)]. Within a similar time frame, a stable VIP analog, stearyl-Nle ¹⁷-VIP (SNV) (42, 43) was designed. SNV interacts with specific GTP-insensitive

Concluding remarks

Peptide-derived molecules provide a conceptual breakthrough for future identification of small molecules that mimick the activity of large protein factors. In addition, they provide a new horizon for innovative drugs to protect the compromised brain using non-invasive intranasal administration. Methods of enhancing drug delivery are currently being tested, and specificity and stability issues are being addressed. Therefore the route to peptide drug discovery might not be too long and

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Trends in Neurosciences

OpinionNeuroprotective peptide drug delivery and development: potential new therapeutics

Abstract

Section snippets

Examples of peptides as drugs

Peptide drug delivery to the brain

Active peptide fragments as neuroprotective agents, our work in the context of others

Concluding remarks

Urology

Prog. Neuropsychopharmacol. Biol. Psychiatry

Nat. Genet.

Curr. Med. Chem.

Stroke

Eur. J. Neurosci.

J. Pharmacol. Exp. Ther.

Drug Target

Methods

Nucl. Med.

Brain Res.

Clin. Pharmacol. Ther.

J. Immunol.

Brain Res.

J. Pharmacol. Exper. Therap.

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

Eur. J. Pharmacol.

J. Pharmacol. Exp. Ther.

J. Neurochem.

J. Biol. Chem.

Regul. Pept.

J. Pharmacol. Exp. Therap.

J. Pharmacol. Exp. Therap.

J. Neurochem.

J. Neurosci.

Soc. Neurosci. Abst.

Rivastigmine, a brain-region selective acetylcholinesterase inhibitor for treating Alzheimer's disease: review and current status

Expert Opin. Investig. Drugs

The parkinsonian models: invertebrates to mammals

Jpn. J. Pharmacol.

Optimal pregnancy outcome in a minimal-stimulation in vitro fertilization program

Am. J. Obstet. Gynecol.

A peptide as a possible transmitter in sympathetic ganglia of the frog

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

Intranasal gonadotropin-releasing hormone (GnRH) therapy for men with idiopathic infertility: GnRH stimulation test may predict response to treatment

Fertil. Steril.

Aqueous vasopressin infusion during chemotherapy in patients with diabetes insipidus

Cancer

Memory deficit in rats with hereditary diabetes insipidus

Brain Res.

Neuromodulation of memory in the hippocampus by vasopressin

Eur. J. Pharmacol.

History and use of oxytocics

Eur. J. Obstet. Gynecol. Reprod. Biol.

Opinion
Neuroprotective peptide drug delivery and development: potential new therapeutics