A Novel CXCR4 Antagonist CX549 Induces Neuroprotection in Stroke Brain

Abstract

C-X-C chemokine receptor type 4 (CXCR4) is a receptor for a pleiotropic chemokine CXCL12. Previous studies have shown that the acute administration of the CXCR4 antagonist AMD3100 reduced neuroinflammation in stroke brain and mobilized bone marrow hematopoietic stem cells (HSCs). The purpose of this study was to characterize the neuroprotective and neurotrophic effect of a novel CXCR4 antagonist CX549. We demonstrated that CX549 had a higher affinity for CXCR4 and was more potent than AMD3100 to inhibit CXCL12-mediated chemotaxis in culture. CX549 effectively reduced the activation of microglia and improved neuronal survival after injury in neuron/microglia cocultures. Early poststroke treatment with CX549 significantly improved behavioral function, reduced brain infarction, and suppressed the expression of inflammatory markers. Compared to AMD3100, CX549 has a higher affinity for CXCR4, is more efficient to mobilize HSCs for transplantation, and induces behavioral improvement. Our data support that CX549 is a potent anti-inflammatory agent, is neuroprotective against ischemic brain injury, and may have clinical implications for the treatment of stroke.

Harnessing CXCR4 antagonists in stem cell mobilization, HIV infection, ischemic diseases, and oncology

“…In comparison with AMD3100, compound 131 exerts better mobilization of HSCs for transplantation and induces behavioral improvement. These in vivo data support that it is a potent anti‐inflammatory agent with great neuroprotective potential against ischemic brain injury, and exhibit clinical implications for the treatment of stroke …”

“…Chronic nonhealing foot ulcers are the common causes of nontraumatic amputation and hospitalization among diabetics in the developed world. Different studies have shown that delayed wound closure is associated with diminished circulating PGCs in diabetic mice . Plerixafor TM improved diabetes associated pathology by reducing bone marrow CXCL12 levels, enhancing PGCs mobilization, and accelerating the wound healing process .…”

“…Besides tissue plasminogen activator (tPA), a protease involved in the breakdown of blood clots, there is no drug approved for improvement of neurologic functions . From a recent study, intermittent administration with CXCR4 antagonists, such as Plerixafor TM or CX549, for three to five consecutive days significantly decreased blood–brain barrier disruption, suppressed inflammation, reduced brain infarction volume, and improved behavioral function after middle cerebral artery occlusion (MCAO) . However, intermittent treatment with Plerixafor TM for seven consecutive days after permanent MCAO reduced migration of PGCs to injured region, decreased capillary density, and attenuated functional recovery …”

“…Different studies have shown that delayed wound closure is associated with diminished circulating PGCs in diabetic mice. 171,172 Plerixafor TM improved diabetes associated pathology by reducing bone marrow CXCL12 levels, enhancing PGCs mobilization, and hence increasing both angiogenesis and vasculogenesis. 181 Also, the endogenous strategy involving a combination of Plerixafor TM and platelet-derived growth factor (PDGF)-BB could synergistically improve PGCs mobilization and trafficking to wound region, thereby significantly enhancing neovascularization and repair of diabetic chronic wound.…”

“…In a recent effort to characterize the neuroprotective and neurotrophic effects of a novel CXCR4 antagonist CX549 (131), it was shown that 131 effectively reduced the activation of microglia and improved neuronal survival after injury in neuron/microglia cocultures. 172 From MCAo rat model studies, early poststroke treatment with 131 could significantly improve behavioral function, reduce brain infarction, and suppress expression of inflammatory markers. In comparison with AMD3100, compound 131 exerts better mobilization of HSCs for transplantation and induces behavioral improvement.…”