Depression is one of the most commonly seen psychiatric diseases in the population
in recent years. Treatment of depression is mainly carried out by psychiatric drugs. In
the past few years, agomelatine which is released to the market with a trade name,
Valdoxane, has been thought to have far less side effects due to its non-addictive
nature, not having trouble when the drug is quitted, and also due to its property of
binding only to the specific receptor that the drug interacts with. The action
mechanism of agomelatine on the membrane structure has not been clarified yet, for
instance, no study has been found in the literature about the interaction of agomelatin
with the lipids of biological membranes. In this current study, the interaction of
agomelatine with the model membranes of dipalmitoylphosphatidylcholine (DPPC),
dipalmitoylphosphatidylgylcerol (DPPG) and sphingomyelin (SM) is examined by
Fourier transform infrared spectroscopy (FTIR) and Differential scanning
calorimetry (DSC).
DSC and FTIR studies show that, agomelatine shifts the phase transition temperature
of DPPC and DPPG multilamellar membrane to the lower degrees, however, it shifts
the phase transition temperature of SM membrane to the higher degrees.
Agomelatine addition increases the lipid order of the DPPC and SM liposome,
whereas, it decreases the lipid order of DPPG liposome. Moreover this drug
enhances the membrane fluidity among all types of liposome studied. The increase of
v
lipid order and increase of fluidity at DPPC and SM liposome indicates domain
formation upon drug addition (Vest et al., 2004). This was also confirmed by DSC
studies.
Agomelatine enhances H bonding capacity of all types of liposomes have been
studied. However it has different effects on glycerol backbones of the DPPC and
DPPG liposomes. At low agomelatine concentrations the increase in the frequency
values indicates a decrease in the hydrogen bonding capacity of the glycerol skeleton
of DPPC. In contrast, at high concentrations of agomelatine, a decrease in the
frequency values was observed as an indicator of the enhancement of the hydrogen
bonding capacity. So it enhances H-bonding capacity at gel phase but lowers it at
liquid chrystalline phases. A progressive decreases in Tm was observed at DPPG and
DPPC liposomes where it increased the Tm at SM. The pretransition peak is
abolished and the Tm peak becomes broad, indicating a larger perturbation to the
membrane. These observations indicate the possible interaction of agomelatine with
the head group as well. The shoulder seen at the thermograms of DPPC and DPPC
liposomes at high doses may indicate the lateral phase separation in to drug-rich and
drug-poor domains (D&rsquo / Souza et al., 2009). These results may indicate that
agomelatine is partially buried in the hydrocarbon core of the bilayer, interacting
primarily with the C2-C8 methylene region of the hydrocarbon chains. All these
results highlight the fact that agomelatine interacts around the head group in such a
manner that it destabilizes the membrane architecture to a large extent.
| Identifer | oai:union.ndltd.org:METU/oai:etd.lib.metu.edu.tr:http://etd.lib.metu.edu.tr/upload/12614997/index.pdf |
| Date | 01 October 2012 |
| Creators | Ergun, Seza |
| Contributors | Severcan, Feride |
| Publisher | METU |
| Source Sets | Middle East Technical Univ. |
| Language | English |
| Detected Language | English |
| Type | M.S. Thesis |
| Format | text/pdf |
| Rights | Access forbidden for 1 year |
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