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Nanomedicine in cerebral palsy.

Balakrishnan B, Nance E, Johnston MV, Kannan R, Kannan S - Int J Nanomedicine (2013)

Bottom Line: Nanomaterials such as dendrimers provide opportunities for the targeted delivery of multiple drugs that can mitigate several pathways involved in injury and can be delivered specifically to the cells that are responsible for neuroinflammation and injury.These materials also offer the opportunity to deliver agents that would promote repair and regeneration in the brain, resulting not only in attenuation of injury, but also enabling normal growth.Future directions that would facilitate clinical translation in neonates and children are also addressed.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University; Baltimore, MD, USA.

ABSTRACT
Cerebral palsy is a chronic childhood disorder that can have diverse etiologies. Injury to the developing brain that occurs either in utero or soon after birth can result in the motor, sensory, and cognitive deficits seen in cerebral palsy. Although the etiologies for cerebral palsy are variable, neuroinflammation plays a key role in the pathophysiology of the brain injury irrespective of the etiology. Currently, there is no effective cure for cerebral palsy. Nanomedicine offers a new frontier in the development of therapies for prevention and treatment of brain injury resulting in cerebral palsy. Nanomaterials such as dendrimers provide opportunities for the targeted delivery of multiple drugs that can mitigate several pathways involved in injury and can be delivered specifically to the cells that are responsible for neuroinflammation and injury. These materials also offer the opportunity to deliver agents that would promote repair and regeneration in the brain, resulting not only in attenuation of injury, but also enabling normal growth. In this review, the current advances in nanotechnology for treatment of brain injury are discussed with specific relevance to cerebral palsy. Future directions that would facilitate clinical translation in neonates and children are also addressed.

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Diagrammatic representation of D-NAC treatment in rabbit kits with CP.Notes: Maternal intrauterine infection/inflammation by LPS treatment results in increased proinflammatory cytokines, leading to activated microglia and astrocytes in the fetus. The activated glial cells further secrete proinflammatory cytokines and free radicals, resulting in oxidative injury, maturation arrest of premature oligodendrocytes, and white matter injury. Intravenous administration of D-NAC in CP kits on postnatal day 1 results in uptake of the dendrimer drug conjugates by activated microglia and astrocytes. Once inside the glial cells, NAC increases the GSH level, decreasing the release of proinflammatory cytokines and synthesis of free radicals with restoration of myelination by oligodendrocytes. Thus D-NAC treatment ameliorates the motor deficits in rabbit kits with CP.Abbreviations: D-NAC, dendrimer-N acetyl cysteine; CP, cerebral palsy; LPS, lipopolysaccharide; GSH, glutathione; TNF, tumor necrosis factor; IL, interleukin; NAC, N-acetyl cysteine.
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f2-ijn-8-4183: Diagrammatic representation of D-NAC treatment in rabbit kits with CP.Notes: Maternal intrauterine infection/inflammation by LPS treatment results in increased proinflammatory cytokines, leading to activated microglia and astrocytes in the fetus. The activated glial cells further secrete proinflammatory cytokines and free radicals, resulting in oxidative injury, maturation arrest of premature oligodendrocytes, and white matter injury. Intravenous administration of D-NAC in CP kits on postnatal day 1 results in uptake of the dendrimer drug conjugates by activated microglia and astrocytes. Once inside the glial cells, NAC increases the GSH level, decreasing the release of proinflammatory cytokines and synthesis of free radicals with restoration of myelination by oligodendrocytes. Thus D-NAC treatment ameliorates the motor deficits in rabbit kits with CP.Abbreviations: D-NAC, dendrimer-N acetyl cysteine; CP, cerebral palsy; LPS, lipopolysaccharide; GSH, glutathione; TNF, tumor necrosis factor; IL, interleukin; NAC, N-acetyl cysteine.

Mentions: For dendrimer-NAC conjugates, the NAC is released from dendrimer in a glutathione (GSH)-dependent manner in the cells, decreasing the inflammatory response, decreasing microglial and astrocyte activation, and improving white matter injury in the kits (Figure 2). Four days after intravenous administration of D-NAC, there was a dramatic improvement in motor function of CP kits, which was associated with significant improvement in neuronal injury, myelination, oxidative injury, and inflammation (Figure 3). When NAC was conjugated to the dendrimer, it was 10- to 100-fold more effective than in its free form. More importantly, these studies suggest that targeted, timely, postnatal attenuation of a prenatal brain injury can be effective.41,42 NAC is normally used in very high doses because of the poor bioavailability resulting from protein binding of its –SH groups.62 Moreover, L-cysteine has been shown to have neurotoxic effects, resulting in neuronal death from overactivation of NMDA receptors on neurons.63 Inflammation also causes depletion of GSH in astrocytes, with a loss of their normal neuroprotective role.30 We expect that delivery of NAC specifically to activated astrocytes and microglia will result in suppression of neuroinflammation and oxidative stress along with replenishment of GSH in astrocytes, thereby leading to sustained improvement of myelination, reduction of white matter injury, and improved neurobehavioral outcomes in neonatal mice and rabbits with PVL. Hence, selective delivery of NAC to glial cells may help decrease neuronal toxicity.


Nanomedicine in cerebral palsy.

Balakrishnan B, Nance E, Johnston MV, Kannan R, Kannan S - Int J Nanomedicine (2013)

Diagrammatic representation of D-NAC treatment in rabbit kits with CP.Notes: Maternal intrauterine infection/inflammation by LPS treatment results in increased proinflammatory cytokines, leading to activated microglia and astrocytes in the fetus. The activated glial cells further secrete proinflammatory cytokines and free radicals, resulting in oxidative injury, maturation arrest of premature oligodendrocytes, and white matter injury. Intravenous administration of D-NAC in CP kits on postnatal day 1 results in uptake of the dendrimer drug conjugates by activated microglia and astrocytes. Once inside the glial cells, NAC increases the GSH level, decreasing the release of proinflammatory cytokines and synthesis of free radicals with restoration of myelination by oligodendrocytes. Thus D-NAC treatment ameliorates the motor deficits in rabbit kits with CP.Abbreviations: D-NAC, dendrimer-N acetyl cysteine; CP, cerebral palsy; LPS, lipopolysaccharide; GSH, glutathione; TNF, tumor necrosis factor; IL, interleukin; NAC, N-acetyl cysteine.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3818020&req=5

f2-ijn-8-4183: Diagrammatic representation of D-NAC treatment in rabbit kits with CP.Notes: Maternal intrauterine infection/inflammation by LPS treatment results in increased proinflammatory cytokines, leading to activated microglia and astrocytes in the fetus. The activated glial cells further secrete proinflammatory cytokines and free radicals, resulting in oxidative injury, maturation arrest of premature oligodendrocytes, and white matter injury. Intravenous administration of D-NAC in CP kits on postnatal day 1 results in uptake of the dendrimer drug conjugates by activated microglia and astrocytes. Once inside the glial cells, NAC increases the GSH level, decreasing the release of proinflammatory cytokines and synthesis of free radicals with restoration of myelination by oligodendrocytes. Thus D-NAC treatment ameliorates the motor deficits in rabbit kits with CP.Abbreviations: D-NAC, dendrimer-N acetyl cysteine; CP, cerebral palsy; LPS, lipopolysaccharide; GSH, glutathione; TNF, tumor necrosis factor; IL, interleukin; NAC, N-acetyl cysteine.
Mentions: For dendrimer-NAC conjugates, the NAC is released from dendrimer in a glutathione (GSH)-dependent manner in the cells, decreasing the inflammatory response, decreasing microglial and astrocyte activation, and improving white matter injury in the kits (Figure 2). Four days after intravenous administration of D-NAC, there was a dramatic improvement in motor function of CP kits, which was associated with significant improvement in neuronal injury, myelination, oxidative injury, and inflammation (Figure 3). When NAC was conjugated to the dendrimer, it was 10- to 100-fold more effective than in its free form. More importantly, these studies suggest that targeted, timely, postnatal attenuation of a prenatal brain injury can be effective.41,42 NAC is normally used in very high doses because of the poor bioavailability resulting from protein binding of its –SH groups.62 Moreover, L-cysteine has been shown to have neurotoxic effects, resulting in neuronal death from overactivation of NMDA receptors on neurons.63 Inflammation also causes depletion of GSH in astrocytes, with a loss of their normal neuroprotective role.30 We expect that delivery of NAC specifically to activated astrocytes and microglia will result in suppression of neuroinflammation and oxidative stress along with replenishment of GSH in astrocytes, thereby leading to sustained improvement of myelination, reduction of white matter injury, and improved neurobehavioral outcomes in neonatal mice and rabbits with PVL. Hence, selective delivery of NAC to glial cells may help decrease neuronal toxicity.

Bottom Line: Nanomaterials such as dendrimers provide opportunities for the targeted delivery of multiple drugs that can mitigate several pathways involved in injury and can be delivered specifically to the cells that are responsible for neuroinflammation and injury.These materials also offer the opportunity to deliver agents that would promote repair and regeneration in the brain, resulting not only in attenuation of injury, but also enabling normal growth.Future directions that would facilitate clinical translation in neonates and children are also addressed.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University; Baltimore, MD, USA.

ABSTRACT
Cerebral palsy is a chronic childhood disorder that can have diverse etiologies. Injury to the developing brain that occurs either in utero or soon after birth can result in the motor, sensory, and cognitive deficits seen in cerebral palsy. Although the etiologies for cerebral palsy are variable, neuroinflammation plays a key role in the pathophysiology of the brain injury irrespective of the etiology. Currently, there is no effective cure for cerebral palsy. Nanomedicine offers a new frontier in the development of therapies for prevention and treatment of brain injury resulting in cerebral palsy. Nanomaterials such as dendrimers provide opportunities for the targeted delivery of multiple drugs that can mitigate several pathways involved in injury and can be delivered specifically to the cells that are responsible for neuroinflammation and injury. These materials also offer the opportunity to deliver agents that would promote repair and regeneration in the brain, resulting not only in attenuation of injury, but also enabling normal growth. In this review, the current advances in nanotechnology for treatment of brain injury are discussed with specific relevance to cerebral palsy. Future directions that would facilitate clinical translation in neonates and children are also addressed.

Show MeSH
Related in: MedlinePlus