Phagocytic functions of microglial cells in the central nervous system and their importance in two neurodegenerative diseases: multiple sclerosis and Alzheimer’s disease

Choucair, Nada; Laporte, Vincent; Lévy, Rachel; Arnold, Anne; Gies, Jean-Pierre; Poindron, Philippe; Lombard, Y.

doi:10.2478/s11535-006-0038-y

Cited by 10 publications

(8 citation statements)

References 162 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These results indicate that fewer macrophages were present in the sciatic nerve distal stump of mice deficient in TLR signaling, although the possibility remains that only the levels of expression of CD68 fluctuated. Activation of macrophages has been reported by others to lead to the upregulation of certain receptors, including CD68 (Choucair et al, 2006).…”

Section: Resultsmentioning

confidence: 88%

Toll-Like Receptor Signaling Is Critical for Wallerian Degeneration and Functional Recovery after Peripheral Nerve Injury

Boivin

Pineau²,

Barrette³

et al. 2007

J. Neurosci.

218

208

View full text Add to dashboard Cite

Toll-like receptors (TLRs) bind specific components conserved among microorganisms as well as endogenous ligands produced by necrotic cells, injured axons, and the extracellular matrix. Here, we investigated whether TLRs are involved in regulating the immune response, Wallerian degeneration (WD), and nerve regeneration after sciatic nerve lesion. Early expression of interleukin-1␤ and monocyte chemoattractant protein-1 was compromised in the sciatic nerve distal stump of mice deficient in TLR signaling. In addition, significantly fewer macrophages were recruited and/or activated in the sciatic nerve distal stump of TLR2-, TLR4-, and MyD88-deficient mice compared with wild-type littermates, whereas WD, axonal regeneration, and recovery of locomotor function were impaired. In contrast, animals that received a single microinjection of TLR2 and TLR4 ligands at the site of sciatic nerve lesion had faster clearance of the degenerating myelin and recovered earlier than saline-injected control rats. Finally, rats that had altered innate immune response through dexamethasone treatment exhibited three times more myelin debris in their sciatic nerve distal stump and a significant delay in recovery of locomotor function. Our results provide strong evidence that TLR signaling plays a critical role in orchestrating the innate immune response leading to efficient and rapid clearance of inhibitory myelin debris and nerve regeneration.

show abstract

Section: Resultsmentioning

confidence: 88%

Toll-Like Receptor Signaling Is Critical for Wallerian Degeneration and Functional Recovery after Peripheral Nerve Injury

Boivin

Pineau²,

Barrette³

et al. 2007

J. Neurosci.

218

208

View full text Add to dashboard Cite

show abstract

“…This is consistent with previous reports of PAMAM dendrimers crossing the blood-brain-tumor barrier in models of malignant gliomas (39). An increase in the number of activated microglia and astrocytes, with enhanced phagocytic abilities under pathological conditions, may further facilitate the selective cellular localization of dendrimers in kits with CP (40). Technical and ethical considerations make direct evaluation of the BBB difficult in patients.…”

Section: Discussionmentioning

confidence: 99%

Dendrimer-Based Postnatal Therapy for Neuroinflammation and Cerebral Palsy in a Rabbit Model

et al. 2012

View full text Add to dashboard Cite

Cerebral palsy (CP) is a chronic childhood disorder with no effective cure. Neuroinflammation, caused by activated microglia and astrocytes, plays a key role in the pathogenesis of CP and disorders such as Alzheimer’s disease and multiple sclerosis. Targeting neuroinflammation can be a potent therapeutic strategy. However, delivering drugs across the blood-brain-barrier to the target cells for treating diffuse brain injury is a major challenge. Here, we show that systemically administered polyamidoamine dendrimers localize in activated microglia and astrocytes in the brain of newborn rabbits with CP, but not healthy controls. We further demonstrate that dendrimer-based N-acetyl-L-cysteine (NAC) therapy for brain injury suppresses neuroinflammation and leads to a dramatic improvement in motor function in the CP kits. The well known and safe clinical profile for NAC when combined with dendrimer-based targeting, provides opportunities for clinical translation in the treatment of neuroinflammatory disorders in humans. The effectiveness of the dendrimer-NAC treatment, administered in the postnatal period for a prenatal insult, suggests a window of opportunity for treatment of CP in humans after birth.

show abstract

“…However, delivery of drugs for the treatment of diffuse brain injury in the neonate is a major challenge. Interestingly, since microglia/astrocytes are more phagocytic in this activated state [11], they may also be more amendable to selectively uptake ‘small’ nanoparticles like dendrimers, compared to other cells in the brain [12, 13]. …”

Section: Introductionmentioning

confidence: 99%

Systemic dendrimer-drug treatment of ischemia-induced neonatal white matter injury

Nance

Porambo

Zhang

et al. 2015

Journal of Controlled Release

View full text Add to dashboard Cite

Extreme prematurity is a major risk factor for perinatal and neonatal brain injury, and can lead to white matter injury that is a precursor for a number of neurological diseases, including cerebral palsy (CP) and autism. Neuroinflammation, mediated by activated microglia and astrocytes, is implicated in the pathogenesis of neonatal brain injury. Therefore, targeted drug delivery to attenuate neuroinflammation may greatly improve therapeutic outcomes in models of perinatal white matter injury. In this work, we use a mouse model of ischemia-induced neonatal white matter injury to study the biodistribution of generation 4, hydroxyl-functionalized polyamidoamine dendrimers. Following systemic administration of the Cy5-labeled dendrimer (D-Cy5), we demonstrate dendrimer uptake in cells involved in ischemic injury, and in ongoing inflammation, leading to secondary injury. The sub-acute response to injury is driven by astrocytes. Within five days of injury, microglial proliferation and migration occurs, along with limited differentiation of oligodendrocytes and oligodendrocyte death. From one day to five days after injury, a shift in dendrimer co-localization occurred. Initially, dendrimer predominantly co-localized with astrocytes, with a subsequent shift towards microglia. Co-localization with oligodendrocytes reduced over the same time period, demonstrating a region-specific uptake based on the progression of the injury. We further show that systemic administration of a single dose of dendrimer-N-acetyl cysteine conjugate (D-NAC) at either sub-acute or delayed time points after injury results in sustained attenuation of the ’detrimental’ pro-inflammatory response up to 9 days after injury, while not impacting the ‘favorable’ anti-inflammatory response. The D-NAC therapy also led to improvement in myelination, suggesting reduced white matter injury. Demonstration of treatment efficacy at later time points in the postnatal period provides a greater understanding of how microglial activation and chronic inflammation can be targeted to treat neonatal brain injury. Importantly, it may also provide a longer therapeutic window.

show abstract

Phagocytic functions of microglial cells in the central nervous system and their importance in two neurodegenerative diseases: multiple sclerosis and Alzheimer’s disease

Cited by 10 publications

References 162 publications

Toll-Like Receptor Signaling Is Critical for Wallerian Degeneration and Functional Recovery after Peripheral Nerve Injury

Toll-Like Receptor Signaling Is Critical for Wallerian Degeneration and Functional Recovery after Peripheral Nerve Injury

Dendrimer-Based Postnatal Therapy for Neuroinflammation and Cerebral Palsy in a Rabbit Model

Systemic dendrimer-drug treatment of ischemia-induced neonatal white matter injury

Contact Info

Product

Resources

About