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The Potential for the treatment of depression through the use of brain improvement and repair in

the hippocampal region done using three specific compounds.


McMillan, Preston N

Abstract: Depression is an illness that affects 300 million people worldwide. Current medications
used to treat depression, also known as antidepressants, have proven to be somewhat effective
treatments as opposed to placebo, with 20-40 people out of 100 reporting improvement in
symptoms using placebo, whereas 40-60 report improvement using antidepressants. Let's
clarify, improvement of symptoms does not mean successful treatment, and it certainly does not
mean the patient is cured. Looking at the results above, it is clear that antidepressants are not
very effective. Going further, 50% of people who have been treated for depression suffer a
relapse, and those who have suffered two or more episodes have an 80% chance of having
another depressive episode. Another effect this has is leading people to believe that
antidepressants do not work, creating another hump in getting people with depression
treatment. Untreated depression can lead to numerous harmful behaviors including substance
abuse and suicide. Literature appears to show that there is a noticeable link between cognitive
deficiency, neurological diseases, and neuropsychiatric diseases. Depression appears to be the
most prominent of these neuropsychiatric diseases. Going further, depression has been linked
to decreased white matter in the brain as well as a smaller hippocampus. Current
antidepressants have also been linked to neurogenesis in the hippocampus. Looking at this
information, it can concluded that a drug attempting to trigger neurogenesis in the hippocampus
and improve cognitive function could have applications in the treatment of numerous
neuropsychiatric and neurological diseases. The one being targeted here is going to be
depression. Abnormally low BDNF levels have been observed in depressed patients, and it
appears to partially mediated by treatment. A drug targeting BDNF and other mechanisms for
cognitive improvement would have potential to be highly beneficial. Ginsenoside Rg3 and
Withanolide A have shown potential in this area, and a depression drug with these two active
ingredients would, likely, result in an improvement of symptoms. Another element of depression
and cognitive deficit is inflammation, which could be caused by allergic reactions. A third
compound, Asiaticoside, would have potential in targeting this area.

Introduction:

The potential applications for a cognitive improvement drug are endless. Every neurological and
neuropsychiatric would show improved disease conditions with a drug that repaired the brain in
any way. BDNF(Brain-derived neurotrophic factor), has been shown to both promote and trigger
neurogenesis in the hippocampus as well as aide in neuroprotection and brain white matter
production.(Pauline M, et al. 2016). BDNF has also been shown, in a mice model, to rescue the
memory deficit in an Alzheimer’s mice model, however, the production in that case was
triggered by social interaction.(Huang CC et al. 2014). A drug somehow uptaking and promoting
BDNF production could potentially have similar effects, resulting in potential improvement of
symptoms in Alzheimer’s disease, going further, another study observed that, in treatment
resistant depression, BDNF levels were genetically short due to decreased gene expression.
(Hong W et al. 2014). BDNF being administered externally has also been shown to increase
KCC2 production, which would aide in the treatment of epilepsy. However, externally injected
BDNF is impractical for humans, so internally producing it would be key, compounds that
internally promote the production of BDNF would be beneficial. (Eftekhari et al. 2014). However,
focusing on depression for the moment would be best, considering that it’s well established that
an uptake in BDNF expression would be the most applicable to the hippocampus, the region
that is defected in those with depression and neuropsychiatric illnesses. (A. Tanni et al. 2013,
Mineur Y et al. 2013., MacQueen G et al. 2010, Zhou W et al. 2014). However, an issue with
BDNF has been raised, and in testing, it did not induce neurite outgrowth. Other mechanisms of
action coupled with increased BDNF production would be key treatment.(Tomoharu et al. 2005)
Another key element of depression that is present is inflammation, with some even arguing that
it’s an inflammatory disease.(Berk M. et al. 2013). Depression appears to be associated with
IL-1B production and NF-kB production. Both of these have been shown to be downregulated
by asiaticoside.(Qiu J et al. 2015. Horowitz M et al. 2015. Miklowitz, D et al. 2016., Al-Saeedi, F.
J. 2014).

Theory
Using the three compounds withanolide a, Ginsenoside Rg3, and Asiaticoside in conjunction, it
should be possible to both induce neurogenesis in the human brain by upregulating BDNF in the
brain, all the while stopping inflammation and promoting the production of hippocampal neurons
through Phosphatidylinositol 3’ Kinase uptake in those neurons.(Hwang D et al. 2017)
Admittedly, all three of these compounds do lack a bit of research, but the research that does
exist is quite promising. With withanolide 1 being shown to promote synaptic and neurite
outgrowth as well as cognitive improvement(Kuboyama T et al. 2005), it is also one of the main
active ingredients of the indian herb ashwagandha, which has some notoriety for improving
cognition in people. Depression patients also were observed to show improved symptoms when
taking Donepezil compared to placebo, a medication that uptakes BDNF and improves
cognition.(Pelton G et al. 2008, Yang Y et al. 2016) Outside of the fact that this means that
Donepezil may warrant more attention as a potential antidepressant, it also demonstrates that
Ginsenoside Rg3 could also be effective as a component of an antidepressant. A mice model
demonstrated that Rg3 showed antidepressant effects through the signaling of the BDNF
pathway(You Z et al. 2017). Asiaticoside, of course, as stated earlier, would inhibit two key
pathways of inflammation in the depression, the NF-kb and IL-1b pathways. Along with that,
Asiaticoside also has been shown to reduce allergy induced inflammation as well. (Jiang J et al.
2017). Cutting off the inflammatory effect, promoting BDNF production, and promoting
Phosphatidylinositol 3’ Kinase production in brain cells should cause a huge improvement in the
condition of depressed patients over time along with cognitive improvement. Any drug capable
of all three of these in conjunction would also have multiple applications to nearly
neuropsychiatric illness as well as neurological illnesses.
Conclusion
Withanolide A. Ginsenoside Rg3, and Asiaticoside, together, show a potential to pull this off.
Millions to even billions of people could potentially benefit. Treatment resistant depression
appears to be mediated by BDNF production and, with millions of suicides occurring worldwide
each year, it’s use as an antidepressant has the potential to be unprecedented. However, even if
all three compounds fail, unless they manage to target all pathways that they should target
according to literature, the theory still stands, and another drug, that’s more potent, could be
formulated.

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