Permeating the Blood Brain Barrier and Abrogating the Inflammation in Stroke: Implications for Stroke Therapy
Bentham Science Publishers
Current Pharmaceutical Design, 2012, 18, 3670-3676
Cesar V. Borlonganb,*, Loren E. Gloverb, P.R. Sanbergb and David C. Hessa,*
Cell therapy has been shown as a potential treatment for stroke and other neurological disorders. Human umbilical cord blood (HUCB) may be a promising source of stem cells for cell therapy. The most desired outcomes occur when stem cells cross the blood brain barrier (BBB) and eventually reach the injured brain site. We propose, from our previous studies, that mannitol is capable of dis- rupting the BBB, allowing the transplanted cells to enter the brain from the periphery. However, when the BBB is compromised, the in- flammatory response from circulation may also be able to penetrate the brain and thus may actually exacerbate the stroke rather than af- ford therapeutic effects. We discuss how an NF-kB decoy can inhibit the inflammatory responses in the stroke brain thereby reducing the negative effects associated with BBB disruption. In this review, we propose the combination of mannitol-induced BBB permeation and NF-kB decoy for enhancing the therapeutic benefits of cell therapy in stroke.
Cell therapies are a revolutionary treatment for neurodegenera- tive diseases. Similar to traditional drug therapies, experimentation must determine many factors for the safety and efficacy of stem cell treatments such as the correct dose, delivery route, and optimal time of intervention . Stem cell lines must be validated through mul- tiple laboratories with different animal models before clinical trials can be authorized . This year, the National Institute of Health is studying the safety and efficacy of stem cells used as treatment for stroke in clinical trials at various stages of recruitment and comple- tion . Eight stem cell products are being evaluated in these trials . Laboratory experimentation is crucial to confirm the mecha- nisms by which particular stem cells, like HUCB cells, provide their neuroprotective as well as neuroregenerative effects in stroke treatment [52-56]. The key to maintaining parallel and thus confir- matory experimentation requires the use of standard protocols for stem cell therapies. The experimental design paradigms created by Stroke Therapy Academic Industry Round Table (STAIR) and Stem cell Therapeutics as an Emerging Paradigm in Stroke (STEPS) have developed guidelines imperative to successful trans- lation of stem cell treatments from the lab to the clinic [52-56]. Future work should focus on HUCB cell treatment which includes mannitol and NF- B decoys in small and large animal models. These animal models must be fully tested to determine possible side effects of the inhibition of NF- B. Experiments must isolate the effects of mannitol alone and the NF- B decoy while monitoring the system in vivo. Other transcription factor decoys should also be identified and tested for use with stem cell therapy. Signaling path- ways are complex communication systems that require careful navigation when inhibition is triggered upstream as in the case of NF- B. Guidelines put forth by STAIR and STEPs must be care- fully considered throughout the lab-to-clinic translational process.
Experimentation with mannitol has shown significant im- provement in cell therapy. Mannitol is an effective BBB permeabi- lizer that has been shown to be effective at lower concentrations and may allow for the earlier entry of stem cells into the injured brain. HUCB in conjunction with mannitol and NF- B decoys may serve as a valuable method of neuroprotection and neurorestoration. Additional laboratory studies are warranted to examine the safety and efficacy of the combination of HUCB transplantation with mannitol and NF- B decoys, including optimization of the optimal dosage, route, and timing of delivery of the combination therapy after stroke.
Although this review focuses on stem cells in combination with mannitol and NF- B as a potential therapeutic for ischemic stroke, the same method of BBB permeabilization can similarly be applied to facilitate the entry of therapeutic drugs from the periphery to the diseased brain, while suppressing systemic inflammation. In addi- tion, whereas this review focuses on stroke, other CNS disorders characterized by BBB damage may benefit from the peripheral administration of stem cells with NF- B decoy treatment. DCH is funded by NIH NS 055728.