Down Syndrome Brain & Norepinephrine drugs

I recently received an email from a family with questions regarding the supplements they were using and considering using with their young daughter with Down syndrome. A couple of the supplements that were in the email, I didn't know very much about and hadn't heard of before. So, of course I wanted to research it to be able to share what I found with them and to also know what it is used for, in case it is something we would consider for my little brother.

In Down syndrome there are several concerns with problems in the brain and degeneration in certain parts of the brain. One area of the brain which sees degeneration is the locus coeruleus (LC), which is in the brainstem. LC supplies the hippocampus with norepinephrine (NE), also known as noradrenaline, which is a neurotransmitter that nerve cells use to communicate. The hippocampus also is affected in people with Down syndrome. This degeneration and lack of NE to the hippocampus creates memory problems. As is described in this quote from Stanford University's article,

"Salehi and his colleagues looked at what could be causing the problems in the hippocampus. Normally, as contextual or relational memories are formed, hippocampal neurons receive norepinephrine from neurons in another part of the brain, the locus coeruleus. The researchers showed that, like humans with Down syndrome, the mice in their experiments experienced early degeneration of the locus coeruleus.

 When the locus coeruleus broke down in the study’s mice, the animals failed at simple cognitive tests that required them to be aware of changes in the milieu: For instance, the genetically engineered mice, when placed in the strange environment of an unknown cage, did not build nests. That contrasts with normal mice, which typically build nests in such circumstances."

As is briefly mentioned in the quote above, near the end of 2009 Stanford University's researchers studied LC, low amounts of NE and it's role in the hippocampus and how to positively change the neurodegeneration.

In this study done by researcher Salehi, they used a "pro-drug" (i.e. it's pro towards norepinephrine) to increase the amounts of NE in the brain of mice models of DS. Their results were very good, as can be seen by a quote from the full text of the study (which can be viewed here),

"In this study, we linked marked defects in hippocampally mediated contextual learning in a model of DS to LC dysfunction and demonstrated that these deficits can be restored by treatments targeted at correcting deficient NE neurotransmission."

So, in short, the researchers used a "pro-drug" called Droxidopa (L-threo-dihydroxyphenylserine, L-DOPS) to increase NE levels in the brain.

Droxidopa crosses the Blood-Brain-Barrier (BBB) and then is able to be used where it is most needed.  Droxidopa was used in conjunction with Carbidopa (which is a DOPA decarboxylase inhibitor). Carbidopa is necessary to be given with Droxidopa so that Droxidopa will ONLY work across the BBB and not outside of the brain. This is necessary to get the optimum amounts of NE in the brain, where it is needed and not outside of the brain where Droxidopa will be dopamine and possibly cause adverse effects.

To see an explanation from the full text of the study that explains the above in more technical terms, here is a quote:

    "We used an NE prodrug that readily crosses the blood-brain barrier (BBB). L-Threo3,4-dihydroxyphenylserine (L-DOPS) or droxidopa is a synthetic amino acid (34). L-DOPS is metabolized by L-aromatic amino acid decarboxylase within NE-containing neurons to yield NE."

By using Droxidopa (along with Carbidopa), the researchers were successfully able to substantially increase hippocampal NE concentrations in mice models of Down syndrome and therefore have greatly improved memory functions & capabilities.

The researchers are now hoping to be able to start clinical trials of Droxidopa on people with Down syndrome, so that it can be approved for use in people with DS. The hope of the Stanford researchers is that by giving Droxidopa and increasing NE concentrations, neurodegeneration may be able to be stopped, or slowed and therefore increase memory function & capabilities.

Their hope is also that it will be helpful to be used in people with Ds who are older and already have large amounts of degeneration and be able to target the still functioning parts of the neurons. Here is a quote from the full text of the study which Stanford researchers did (Restoration of norepinephrine-modulated contextual memory in a mouse model of Down syndrome.) that discusses the above,

"The most important implication of our work is that postsynaptic targets of degenerating neurons
may remain responsive and functional well after the presence of advanced disease in their presynaptic inputs. If so, treatments that target still-functional elements of neuronal circuits may restore circuit function. In particular, treatments targeted to restore the loss of NE inputs to the hippocampus may prove effective in enhancing cognition in people in whom these neurons are affected."

And, here is another interesting quote from the full text of this study. This quote below shows just how well their results were in the DS mouse models.

"Indeed, NE release from LC axons may play a defining role in cholinergic and serotoninergic
neurotransmission. Given the degeneration of these other neuronal systems in the Ts65Dn mouse as well as in DS and AD, it might be argued that dysfunction of the LC represents only one of several deficiencies and that rescuing NE concentrations would have no effect on cognition. Our data argue that this is not the case. Instead, they indicate that restoring NE neurotransmission is effective even when these other neurons are affected."

Another quote from the study, which summarizes what has been said above:

"In this study, two agents acted to restore contextual learning. In the case of L-DOPS, the drug is metabolized by LC terminals to produce NE......If this circumstance also applies to humans, restoring NE concentrations in the hippocampus may act to enhance contextual learning even in patients in which LC degeneration is advanced."

And one final quote from the study,

"Our findings suggest that enhancing NE neurotransmission may be useful in treating cognitive disability in DS. An important question is which age group to target. The murine studies reported herein suggest that young adults with DS, in whom pathology is present but not advanced, may be appropriate. If the status of LC neurons and their targets in mice mirrors those in humans, at this stage of the disorder postsynaptic adrenergic receptors will be present and responsive to
pharmacologically induced increases in brain NE concentrations. We envision a plan to test the efficacy of droxidopa in young adults with DS."

Now, the question is, do we supplement our children with L-DOPS, because of the positive outcomes of the study? It's a tough question.

I am one of those people who will look at a study and act upon the results. We've done it numerous times. That's why we give O Longvida Curcumin, Nutrivene-D, Ginkgo Biloba, etc. Because we've seen what the study says and we put the puzzle together - by doing this & giving this, an improvement was seen here, so let's do that!

From the research I have done so far, I see no harm in giving L-DOPS to increase NE levels. I see a lot of benefit.

Personally, I have a hesitancy with it still, because it is a drug and is a synthetic amino acid precursor. If you've been reading this blog for any length of time, you'll know that we have a hesitancy with taking drugs (hence the reason why O does not take Prozac, as is recommended by the Changing Minds Foundation). So, that is the only reason why and where my hesitation comes from.

I will continue to research L-DOPS/Droxidopa and ways to increase NE levels and share what I find, if I find anything else of interest. There are a few things I have taken down in a note to look at further as well, just in finding out other ways that NE deficiency is connected in Down syndrome.

There are some other thoughts and things I want to research in regards to possible ways to increase NE by using L-tyrosine, and using a natural DOPA decarboxylase inhibitor like EGCG, but that will have to wait for another day.