Colivelin
Now Available!
Though the cause of
Alzheimer’s Disease (AD) is probably due to multiple factors, increasing
evidence indicates accumulation of amyloid
b
(Ab)
is a major event contributing to neuronal death and disease progression.
Recent therapies have focused on use of agents that can decrease amyloid
b
levels and use of neuroprotective agents. Humanin (PHN-4384-v)
is a short polypeptide which was shown to have neuroprotective effects
against four representative familial AD (FAD) genes and Ab
peptides (1). Since then, additional humanin derivatives with greater
neuroprotective effects have been developed with AGA-(C8R)HNG17 being the
most potent (2). Most recently, Chiba and colleagues
developed a new hybrid peptide named colivelin with even greater
neuroprotective ability by attaching activity-dependent neurotrophic factor
(ADNF) to the C-terminus of AGA-(C8R)HNG17. 2 ADNF was
first isolated from astrocyte media and was shown to be neuroprotective
against AD and non AD related toxic agents (3). ADNF can
suppress Ab
toxicity at 100 fM
but loses its protective activity at or above nanomolar concentrations (4).
Colivelin was shown to be neuroprotective against AD toxicities in
vitro and in vivo and can protect against non AD toxicities as
well. It is 100x more potent than AGA-(C8R)HNG17 alone and 100,000,000x
more potent than humanin. In addition, colivelin does not lose its
neuroprotective function at higher concentrations as does ADNF. Colivelin
was also shown to block Ab1-42
and Ab25-35
impairment of spatial memory and suppress 3-quinuclidinyl benzilate induced
memory impairment, suggesting it can pass through the blood-brain barrier.
Humanin
In 2001, humanin was identified by a group of scientists in
Tokyo, Japan. Its discovery was facilitated by first isolating a gene that appears to
provide protection against forms of Alzheimer’s Disease (AD) (5,6).
Activity of endogenous humanin was
improved by 1000 fold with glycine replacement at position 14.
Humanin
was found to protect against cell death in tissues containing certain mutations, including
one known as the Swedish mutant. These mutant genes are believed to be responsible for
early-onset of Familial Alzheimer’s Disease (FAD). While the exact mechanisms by
which humanin exerts its actions are not known, this
discovery provides a potentially exciting approach for treating AD. Further studies will
be required to validate these initial promising results and to determine if modifications
of the fragile peptide into a more robust, drug-like molecule might offer new hope for AD
therapy. As with insulin, peptides such as humanin are
typically rapidly degraded by gastrointestinal enzymes, and thus would likely be
administered by injection. Peptides are also costly to produce, although economies of
scale can substantially decrease these costs when peptides enter into large scale
production.
Peptides International
now offers colivelin as a new exciting tool for the study of Alzheimers’
Disease and possibly other neurodegenerative diseases since most recent
findings indicate humanin may also offer neuroprotection against stroke (7).
1. Y. Hashimoto, T.
Niikura, H. Tajima, T. Yasukawa, H. Sudo, Y. Ito, Y. Kita, M. Kawasumi, K.
Kouyama, M. Doyu, G. Sobue, T. Koide, S. Tsuji, J. Lang, K. Kurokawa, and I.
Nishimoto, Proc. Natl. Acad. Sci. USA, 98, 6336 (2001).
2.
T. Chiba, M.
Yamada, Y. Hashimoto, M. Sato, J. Sasabe, Y. Kita, K. Terashita, S. Aiso, I.
Nishimoto, and M. Matsuoka, J. Neuroscience, 25, 10252 (2005).
3. D.E. Brenneman
and I. Gozes, J. Clin. Invest., 97, 2299 (1996).
4. D.E. Brenneman,
J. Hauser, E. Neale, S. Rubinraut, M. Fridkin, A. Davidson, and I. Gozes,
J. Pharmacol. Exp. Ther., 285, 619 (1998).
5. Y. Hashimoto, T. Niikura, H. Tajima, T. Yasukawa, H. Sudo, Y. Ito, Y. Kita, M.
Kawasumi, K. Koumaya, M. Doyu, G. Sobue, T. Koide, S. Tsuji, J. Lang, K. Kurokawa, and I.
Nishimoto, Proc. Natl. Acad. Sci. U.S.A., 98, 6336 (2001). (Original,
Humanin)
6. Y. Hashimoto, Y. Ito, T. Niikura, Z. Shao, M. Hata, F. Oyama, and I. Nishimoto Biochem.
and Biophys. Res. Comm., 283, 460-468 (2001). (Pharmacol.
Humanin)
7. X. Xu, C.C. Chua,
R.C. Hamdy, and B.H.L. Chua, Society for Neuroscience 35th
Annual Meeting, (2005).
Other related references:
T. Mamiya and M. Ukai, Br. J. Pharmcol., 134, 1597 (2001). (Pharmacol.)
S. Kariya, N. Takahashi, N. Ooba, M. Kawayama, H. Nakayama, and S. Ueno, Neurochemistry,
13, 903 (2002). (Pharmacol.)
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