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Dendrimers deliver relief for cerebral palsy?

May 8, 2012

Holy smokes! It’s been almost 3 months since I last posted. This is not for wont of interesting articles; rather, I have been wedding planning! All of the important things are complete now (dress, venue, fiance) so I hope it will not be 3 more months until I bring you the next article. Today’s article comes from the April 18 issue of Science Translational Medicine and suggests a very promising treatment for cerebral palsy.

First, let’s briefly talk about inflammation. Although inflammation has many useful effects during an infection (recruiting  our immune cells, damaging the pathogen), many of the responses are indiscriminate grenades that kill invaders as well as host cells. Since inflammation can be dangerous to self, three organs have what is called immunological privilege. The robust immune responses  typical of other organs do not occur in privileged organs, such as the intestines. Inflammation would reduce intestinal function, so inflammation is normally “turned off” in the intestines. The second immunologically privileged organ is the brain. Inflammation is incredibly damaging to the brain and is responsible for the deaths of people with meningitis. For this reason, immune cells circulating in blood are typically prevented from entering the brain at the blood-brain barrier where blood and brain tissue are in close contact.

Now, what is cerebral palsy?
Prior to writing this, I was admittedly poorly informed about cerebral palsy, thinking it stemmed solely from oxygen deprivation at birth and caused always-devastating developmental delays and wheelchair confinement. However, cerebral palsy has diverse causes and outcomes and is an umbrella term that describes a variety of motor disabilities ranging in severity. Cerebral palsy can be caused by brain damage due to a lack of oxygen at delivery, but can also be caused by infections during pregnancy which create an inflammatory environment around the fetus. Are you surprised to learn that the placenta is the third organ with immunological privilege? Uterine inflammation activates special immune cells in the brain, microglia, and creates an inflammatory environment in the developing baby’s brain before and after birth.  Unfortunately, cerebral palsy usually goes undetected until the age of 2 or 3, when a child’s failure to develop normal motor skills becomes apparent.

How can cerebral palsy be examined experimentally? 

Kannan and coauthors used a rabbit model of cerebral palsy. In this experiment, a toxin from E. coli was injected near the uterus of pregnant rabbits 3 days before their pregnancies were full-term. Toxin-exposed kits (baby rabbits) have many of the classic symptoms of cerebral palsy. Inflammation causes nerves to become demyenlinated, preventing them from sending signals properly and impairing motor function, and the activation of those microglia causes the death of neurons. All of this leads to the poor locomotion and muscle rigidity that is characteristic of both rabbit and human cerebral palsy.

How did the authors treat it?
The molecule N-acetyl-L-cysteine (“NAC” to us) has many neuro-protective effects. The authors combined NAC with a molecular called a dendrimer which acts as a vehicle, essentially encapsulating the NAC until it is absorbed by cells. The microglia, which were formally pro-inflammatory, became anti-inflammatory after absorbing the dendrimer-NAC combination. But wait, shouldn’t the blood-brain barrier prevent compounds from crossing from the blood into those brain cells?! Well, the inflammation that has already been set off in the brain makes the blood-brain barrier “leaky,” and allows the drug to cross. For this reason, the normally-developing rabbit kits in the control group (no toxin exposure) did not absorb any of the drug.

After injecting the drug on the kits’ birthday, the authors followed the kits’ progress for 5 days. At day 1, indicators of inflammation was high and kits had poorer motor skills than control animals. However, by day 5, kits receiving the drug had recovered normal motor function and inflammation levels! Their muscles were no longer hyper-rigid and they gained weight on pace with control kits.

Can this drug be used to treat human cerebral palsy?
In this world of pessimism and careful phrasing, I was actually surprised how optimistic the authors seemed in their conclusions. The dendrimers used in this study apparently cause no adverse health effects, even at 10x the maximum dose used in this study. However, the authors administered the dendrimer-NAC combination during a crucial phase of rabbit brain development whereas human cerebral palsy typically goes undetected until 2-3 years of age. The authors understandably advocate for early detection of inflammation in the brain via noninvasive PET or MRI exams. Human babies at risk for cerebral palsy would very likely need repeat doses of a drug such as NAC, but this study appears to be a very promising treatment for not only cerebral palsy, but other neuro-inflammatory disorders, including Alzheimer’s disease and autism.

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