The synthetic peroxisome proliferator-activated receptor-gamma agonist ciglitazone attenuates neuroinflammation and accelerates encapsulation in bacterial brain abscesses.

Brain abscesses result from a pyogenic parenchymal infection commonly initiated by Gram-positive bacteria such as Staphylococcus aureus. Although the host immune response elicited following infection is essential for effective bacterial containment, this response also contributes to the significant loss of brain parenchyma by necrosis that may be reduced by modulating the inflammatory response. Ciglitazone, a PPAR-gamma agonist with anti-inflammatory properties, was evaluated for its ability to influence the course of brain abscess development when treatment was initiated 3 days following infection. Interestingly, abscess-associated bacterial burdens were significantly lower following ciglitazone administration, which could be explained, in part, by the finding that ciglitazone enhanced S. aureus phagocytosis by microglia. In addition, ciglitazone attenuated the expression of select inflammatory mediators during brain abscess development including inducible NO synthase, TNF-alpha, IL-1beta, CXCL2, and CCL3. Unexpectedly, ciglitazone also accelerated brain abscess encapsulation, which was typified by the heightened expression of fibronectin and alpha-smooth muscle actin-positive myofibroblasts. Collectively, through its ability to attenuate excessive inflammation and accelerate abscess encapsulation, ciglitazone may effectively sequester brain abscesses and limit bacterial dissemination.

Minocycline modulates neuroinflammation independently of its antimicrobial activity in staphylococcus aureus-induced brain abscess.

Minocycline exerts beneficial immune modulatory effects in several noninfectious neurodegenerative disease models; however, its potential to influence the host immune response during central nervous system bacterial infections, such as brain abscess, has not yet been investigated. Using a minocycline-resistant strain of Staphylococcus aureus to dissect the antibiotic's bacteriostatic versus immune modulatory effects in a mouse experimental brain abscess model, we found that minocycline significantly reduced mortality rates within the first 24 hours following bacterial exposure. This protection was associated with a transient decrease in the expression of several proinflammatory mediators, including interleukin-1beta and CCL2 (MCP-1). Minocycline was also capable of protecting the brain parenchyma from necrotic damage as evident by significantly smaller abscesses in minocycline-treated mice. In addition, minocycline exerted anti-inflammatory effects when administered as late as 3 days following S. aureus infection, which correlated with a significant decrease in brain abscess size. Finally, minocycline was capable of partially attenuating S. aureus-dependent microglial and astrocyte activation. Therefore, minocycline may afford additional therapeutic benefits extending beyond its antimicrobial activity for the treatment of central nervous system infectious diseases typified by a pathogenic inflammatory component through its ability to balance beneficial versus detrimental inflammation.

Combining an autologous peripheral nervous system "bridge" and matrix modification by chondroitinase allows robust, functional regeneration beyond a hemisection lesion of the adult rat spinal cord.

Chondroitinase-ABC (ChABC) was applied to a cervical level 5 (C5) dorsal quadrant aspiration cavity of the adult rat spinal cord to degrade the local accumulation of inhibitory chondroitin sulfate proteoglycans. The intent was to enhance the extension of regenerated axons from the distal end of a peripheral nerve (PN) graft back into the C5 spinal cord, having bypassed a hemisection lesion at C3. ChABC-treated rats showed (1) gradual improvement in the range of forelimb swing during locomotion, with some animals progressing to the point of raising their forelimb above the nose, (2) an enhanced ability to use the forelimb in a cylinder test, and (3) improvements in balance and weight bearing on a horizontal rope. Transection of the PN graft, which cuts through regenerated axons, greatly diminished these functional improvements. Axonal regrowth from the PN graft correlated well with the behavioral assessments. Thus, many more axons extended for much longer distances into the cord after ChABC treatment and bridge insertion compared with the control groups, in which axons regenerated into the PN graft but growth back into the spinal cord was extremely limited. These results demonstrate, for the first time, that modulation of extracellular matrix components after spinal cord injury promotes significant axonal regeneration beyond the distal end of a PN bridge back into the spinal cord and that regenerating axons can mediate the return of useful function of the affected limb.

Radiation-induced modulation of the microglial population in the normal and injured mature spinal cord.

Recent attempts by other investigators to enhance repair processes in the spinal cord have involved the administration of X rays to spinal cord injury sites. Although some functional improvement has been reported, the underlying cellular changes within the irradiated spinal cords are not clear. Studies initiated recently in this laboratory examined the potential of X rays to modulate nonneuronal cell populations associated with an injury site in adult mammalian spinal cords. These studies revealed a unique and previously unreported radiosensitivity of the microglial cell population. Administration of X radiation to a unilateral dorsal lesion cavity in the cervical spinal cord revealed a significant decrease (approximately half) in numbers of microglia associated with the cavity. Even more unexpected were the significant decreases in microglial cells observed on the nonlesioned side of the spinal cord or in sham-operated spinal cords in irradiated rats. In contrast to reports of others, densitometric quantification of GFAP immunoreactive cells and processes indicated no differences in the astrocytic reactions associated with the lesion cavities between nonirradiated and irradiated groups in our studies. The demonstration that exposure of a spinal cord injury site to radiation modifies the responses of certain components of the glial environment to injury may offer a noninvasive approach for direct treatment of that site. Studies are in progress to determine if this altered glial environment enhances the extension of regrowing axons from a peripheral nerve graft across the interface with the irradiated lesion cavity and into the spinal cord parenchyma.