Spelling suggestions: "subject:"neuroblastoma SH-SY5Y cells"" "subject:"neuroblastome SH-SY5Y cells""
1 |
Novel norbornane derivatives as potential neuroprotective agentsEgunlusi, Ayodeji Olatunde January 2020 (has links)
Philosophiae Doctor - PhD / Neurodegenerative disorders are characterised by progressive loss of the brain’s physiological
functions as a result of gradual degeneration of neurons in the central nervous system. Even
though they are classified as diseases of the elderly, occurrence earlier in life is possible, but
that would suggest the influence of genetic and/or environmental factors. Due to the continuous
rise in modernisation and industrialisation over the years, there has been an increase in
incidence and prevalence of neurodegenerative disorders. With the advances in technology and
life expectancy, the rates of the common forms (Alzheimer’s disease and Parkinson’s disease),
are expected to increase exponentially by 2050. Unfortunately, there is still no clinically
approved treatment or therapy to slow down or halt the degenerative process as most registered
drugs only offer symptomatic relief. Confounding this issue is the lack of definite mechanism
of neurodegeneration, which is still poorly defined and not completely understood.
Nonetheless, the pathology of most neurodegenerative disorders is believed to be a
combination of interrelated processes that eventually leads to neuronal cell death. Among the
postulated processes, the impact of excitotoxicity mediated by NMDA receptor over-activation
is prominent and it is implicated in virtually all neurodegenerative disorders. With this basic
insight, it is believed that molecules capable of inhibiting NMDA receptors and associated
calcium channels, without affecting the normal physiological functions of the brain, could
potentially serve as good neuroprotective drugs. Competitive and uncompetitive blockers
(MK-801 and ketamine) have been explored, but none were clinically accepted due to
undesirable side effects such as hallucinations, sedation and depression. However, NGP1-01,
a polycyclic cage molecule, has been shown to be neuroprotective through modulation of
NMDA receptors and voltage gated calcium channels and attenuation of MPP+
-induced
toxicity. A similar approach could be useful in the design and development of new
neuroprotective drugs.
The aim of this study was to synthesise a series of open and rearranged cage-like molecules
and explore their neuroprotective potential in neuroblastoma SH-SY5Y cells. The proposed
structures, with norbornane scaffolds that contained different moieties, were designed to
structurally resemble NGP1-01 and MK-801. Once synthesised, the compounds were purified
and characterised, and were evaluated for their biological activities. Compounds were first
screened for cytotoxicity at different concentrations. Thereafter, they were evaluated for
neuroprotective effects against MPP+
-induced excitotoxicity and for calcium flux modulatory
effects on NMDA receptor and voltage gated calcium channels.
The norbornane derivatives were synthesised and characterised, and all final products were
afforded in sufficient yields. All compounds with the exception of two compounds displayed
good cytotoxic profiles towards the SH-SY5Y neuroblastoma cells at 10 µM, 50 µM and 100
µM concentrations as they demonstrated percentage cell viabilities close to 100% (control
treated cells). Only two compounds showed percentage cell viability of 51% and 59% at 100
µM. Utilising the same cell line, all compounds, tested at 10 µM, attenuated MPP+
-induced
toxicity after 24 hours of exposure to a neurotoxin. This was evident in the 23% to 53%
enhancement (significant with p < 0.05) in cell viability when compared to the MPP+
only
treated cells. In comparison to known NMDA receptor and/or voltage gated calcium channel
blockers (MK-801, NGP1-01 or nimodipine), the synthesised compounds demonstrated mono
or dual inhibition of calcium channels as they effectively attenuated calcium influx by blocking
NMDA receptors and/or voltage gated calcium channels expressed in neuroblastoma SHSY5Y cells. This group of compounds were found to be more potent NMDA receptor
inhibitors, probably due to similarities with MK-801 and memantine, than voltage gated
calcium channel inhibitors. All compounds demonstrated moderate to good calcium inhibitory
effects at NMDA receptors in the range of 23% to 70% while a selected few displayed very
little or no activity at the voltage gated calcium channels.
In conclusion, 27 compounds with norbornane scaffolds were successfully synthesised and
evaluated for cytotoxicity and neuroprotection. The abilities of the synthesised compounds to
protect neurons from the neurotoxin MPP+
and reduce calcium flux into neuronal cells were successfully demonstrated. These characteristics are essential in neuroprotection as they may prove significant in halting or slowing down the disease progression. The compounds showing a good cytotoxicity profile, neuroprotective effects and ability to reduce calcium overload,
could potentially act as neuroprotective agents with good safety profiles or contribute as lead
structures to the development and design of structurally related molecules that could clinically
benefit people with neurodegenerative disorders.
|
Page generated in 0.0497 seconds