Dendrimers for brain treatment
A group of scientists from Johns Hopkins University and other research centers working under the leadership of Dr. Rangaramanujam Kannan has developed nanocomplexes capable of penetrating the blood-brain barrier and delivering a drug that suppresses inflammation that destroys the brain of rabbits with simulated cerebral palsy (cerebral palsy).
Cerebral palsy develops in about 3 out of 1000 newborns as a result of infection or oxygen deficiency before, during or immediately after childbirth. Often this disease leads to severe disability. Existing therapies are aimed at alleviating symptoms and improving the quality of life, but they are not able to reduce or restore neurological damage and motor function disorders.
Inflammatory damage to nervous tissue occurs when microglial cells and astrocytes – auxiliary cells of brain tissue, one of the functions of which is to protect nervous tissue from infections and inflammation – show excessive activity and destroy not only already damaged, but also healthy nerve cells.
Direct impact on brain cells is an extremely difficult problem due to the existence of biological and physiological systems formed during evolution that protect the brain from infectious agents entering the bloodstream. Another task was to develop an approach that would ensure the selective delivery of an anti-inflammatory drug to out-of-control cells.
At the same time, the use of dendrimers – symmetrically branching synthetic macromolecules, whose size is 2000 times smaller than the diameter of an erythrocyte, made it possible to solve these two difficult tasks. The small size allows dendrimers to penetrate the blood–brain barrier, and the tree-like structure allows them to attach a large number of drug molecules to their surface.
As a therapeutic agent, the researchers used N-acetyl-L-cysteine, an anti–inflammatory drug used as an antidote for poisoning with acetaminophen (paracetamol).
In addition, fluorescent tags were attached to dendrimers made of polyamidoamine, a substance often used to create tree–like polymers, allowing tracking the movement of the entire complex in the body. The resulting structures were injected into rabbits with cerebral palsy six hours after birth. Only N-acetyl-L-cysteine was injected into the control group animals.
The observation showed that the nanostructures not only penetrated into the brain tissue, but were also rapidly absorbed by hyperactive astrocytes and microglial cells.
The result of this was a significant improvement in motor functions in newborn animals, which by the fifth day of observation practically did not differ from healthy baby rabbits. At the same time, the animals of the control group showed practically no improvement even with the administration of a dose of N-acetyl-L-cysteine, 10 times higher than that contained in the dendrimer complex.
The figure on the left shows a schematic image of a dendrimer with numerous appendages to which the molecules of the drug and the fluorescent label are attached.
On the right – activated microglial cells in the brain tissue (red) of a rabbit with cerebral palsy, absorbed dendrimers (green).
Analysis of brain tissue showed that therapy with dendrimer complexes significantly reduced the number of hyperactive cells and reduced the levels of other markers of inflammation. The animals of the experimental group were also characterized by better preservation of myelin, a protein of the protective shell of axons that is damaged in cerebral palsy and other neurological diseases. Another important result was the preservation of a larger number of neurons in the brain centers responsible for coordination and control of motor function, compared with the control group and untreated animals.
The data obtained indicate that the proposed method of therapy not only selectively suppresses inflammatory processes, but also prevents damage and death of nerve cells. In order to make sure that the therapeutic effects are irreversible, the researchers plan to observe the animals until they reach adulthood. They believe that dendrimer complexes can be useful in the treatment of other neurological diseases of humans, the pathogenesis of which involves inflammatory processes of nervous tissue, including Alzheimer's disease, stroke, autism and multiple sclerosis.
A separate study, also conducted under the direction of Dr. Kannan, has already demonstrated the therapeutic effectiveness of the developed approach in eliminating retinal damage in rats with macular degeneration, a disease that is one of the leading causes of vision loss in old age.
Article by Sujatha Kannan et al. Dendrimer-Based Postnatal Therapy for Neuroinflammation and Cerebral Palsy in a Rabbit Model is published in the journal Science Translational Medicine.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on Johns Hopkins Medicine: Nano-Devices that Cross Blood-Brain Barrier Open Door to Treatment of Cerebral Palsy, Other Neurological Disorders.
26.04.2012