Abstract: Maraviroc (UK-427857) is a selective, orally bioavailable C-C chemokine receptor type 5 (CCR5) antagonist originally developed and approved for the treatment of R5-tropic human immunodeficiency virus type 1 (HIV-1) infections. Recently, its therapeutic potential has expanded significantly into the field of neurology. Preclinical and clinical evidence indicates that CCR5 plays a critical role in neuroinflammation, neuropathic pain, and brain injury. By blocking this receptor, maraviroc has demonstrated robust neuroprotective and recovery-enhancing effects in models of stroke, traumatic brain injury (TBI), and intracerebral hemorrhage. Furthermore, it has shown efficacy in diminishing neuropathic pain, enhancing opioid analgesia, and protecting the blood-brain barrier from viral-induced endothelial dysfunction. This review synthesizes the current literature on maraviroc's pharmacological activity, molecular mechanisms, structure-activity relationships, current limitations, and future perspectives in neurological applications.
1. Introduction
Maraviroc (UK-427857) is a small-molecule drug that was discovered and developed as a first-in-class host-targeted antiretroviral therapy for HIV-1 [4]. It exerts its primary effect by selectively antagonizing the CCR5 receptor, a critical co-receptor for the entry of R5-tropic HIV-1 into host cells [4]. Beyond its established role in infectious disease, recent research has highlighted the profound involvement of the CCR5 receptor in the central nervous system (CNS) and peripheral nervous system (PNS). CCR5 is expressed on various cell types within the brain, including neurons, microglia, astrocytes, and endothelial cells [5]. Following nervous system injury, the upregulation of CCR5 and its endogenous ligands (such as CCL3, CCL4, and CCL5) drives neuroimmunological changes that contribute to secondary brain damage, neuroinflammation, and pain hypersensitivity [2]. Consequently, maraviroc has emerged as a highly promising candidate for repurposing in neurology, with investigations spanning stroke recovery, traumatic brain injury (TBI), neuropathic pain management, and the treatment of neuroinflammatory complications such as progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome (PML-IRIS) [1][2][3][5].
2. Pharmacological Activity
Stroke and Brain Injury: Maraviroc has demonstrated significant cerebroprotective and recovery-promoting effects in various models of brain injury, including TBI, focal cortical stroke, cerebral ischemia-reperfusion injury, and intracerebral hemorrhage [2]. In preclinical stroke models, acute administration of maraviroc (e.g., 1 hour post-stroke) significantly reduces infarct volume and improves motor performance on corner, limb placement, foot fault, and rotarod tests, as well as cognitive outcomes in the Morris Water Maze [5]. Furthermore, subacute and chronic administration (initiated 24 hours to 4 weeks post-stroke) enhances long-term functional recovery on cylinder and grid walk tasks, indicating its role in neural repair [5].
Neuropathic Pain and Analgesia: In models of peripheral nerve injury, such as chronic constriction injury, maraviroc effectively diminishes hypersensitivity to tactile and thermal stimuli [2]. Notably, the administration of maraviroc not only reduces pain symptoms but also enhances the analgesic effectiveness of opioid drugs like morphine and buprenorphine, suggesting a synergistic role in pain management [2].
Neuroinflammation and Endothelial Protection: Maraviroc is neuroprotective against viral-induced damage. In HIV models, it protects the brain vascular endothelium by preventing the loss of tight junction proteins (claudin-5, ZO-1, and ZO-2) and reducing leukocyte infiltration into the brain [1]. It also attenuates HIV-1 Tat-induced neuroinflammation and reduces the activation of brain phagocytes [1]. Clinically, maraviroc has been explored in PML-IRIS, where it is hypothesized to reduce severe neuroinflammation by limiting the trafficking of CCR5+ CD8+ T cells into the CNS [3].
3. Molecular Mechanism of Action
Maraviroc functions as a slow-offset functional antagonist that binds to the transmembrane pocket of the CCR5 receptor, preventing receptor internalization and blocking the binding of both HIV-1 and endogenous pro-inflammatory chemokines [4].
Neuroprotection and Neural Repair: In the context of stroke, maraviroc reduces cell death by increasing the anti-apoptotic Bcl2:BAX ratio and increasing IκBα levels, while simultaneously decreasing the phosphorylation of pro-inflammatory and stress-related pathways (P-IκBα, P-P65, P-P38, and P-JNK) [5]. This leads to a reduction in pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α [5]. To promote recovery, maraviroc enhances neuroplasticity by upregulating CREB, pCREB, and DLK, which translates to an increased dendritic spine count, prevention of spine loss, and enhanced bihemispheric axonal sprouting [5]. It also decreases the recruitment of Ly6C neutrophils and macrophages to the injury site [5].
Pain Modulation: The analgesic effects of maraviroc are mediated through the polarization and suppression of spinal microglia and astroglia [2]. Following nerve injury, activated glial cells release anti-opioid immune factors; by blocking CCR5 on these cells, maraviroc silences these neuroimmunological changes, thereby reducing pain development and preventing the heterologous desensitization of opioid receptors [2].
Blood-Brain Barrier Integrity: Maraviroc protects the blood-brain barrier by preventing the HIV-induced upregulation and phosphorylation of cytoskeleton-associated proteins in endothelial cells. This action diminishes the viral-induced adhesion of monocytes and their transendothelial migration into the brain parenchyma [1].
4. Structure-Activity Relationship (SAR)
Maraviroc was discovered through a high-throughput screening of a vast compound library using a chemokine radioligand-binding assay [4]. The initial hit compound underwent an extensive medicinal chemistry optimization process, during which almost 1,000 molecules were synthesized and characterized [4]. The optimization focused on maximizing potency against the CCR5 receptor, ensuring broad-spectrum antiviral activity, achieving favorable pharmacokinetic characteristics (such as oral bioavailability), and maintaining strict selectivity against other human cellular targets to ensure a clean safety profile [4]. Structurally, maraviroc is tailored to bind deep within the transmembrane pocket of the CCR5 receptor, which induces a conformational state that prevents the receptor from interacting with its natural chemokine ligands or the HIV-1 gp120 envelope glycoprotein [4].
5. Current Limitations
Despite its promise, the translation of maraviroc into neurological clinical practice faces several limitations:
- Preclinical Methodological Gaps: Systematic reviews of maraviroc in stroke models reveal a high risk of bias, including incomplete outcome data and selective reporting [5]. Furthermore, preclinical studies predominantly utilize young, healthy male rodents, failing to account for critical clinical variables such as advanced age, female sex, and common stroke comorbidities (e.g., hypertension and diabetes) [5].
- Pharmacokinetic Translation: Translating effective doses from animals to humans is challenging. For example, a maximum preclinical dose of 100 mg/kg in mice resulted in cerebrospinal fluid (CSF) concentrations of maraviroc that were actually lower than those observed in humans receiving standard clinical doses, complicating the interpretation of dose-response relationships [5].
- Clinical Efficacy Discrepancies: While individual case reports have shown dramatic clinical improvement when maraviroc was used for PML-IRIS, larger controlled studies, such as the CADIRIS trial, demonstrated that the addition of maraviroc to antiretroviral therapy did not reduce the overall risk of IRIS in patients with advanced HIV infection [3].
6. Future Perspectives
The future of maraviroc in neurology is highly active, with several avenues for clinical and preclinical advancement. The ongoing CAMAROS (Canadian Maraviroc Randomized Controlled Trial To Augment Rehabilitation Outcomes After Stroke) trial is currently investigating the efficacy of maraviroc in the subacute post-stroke phase, specifically paired with an 8-week exercise and rehabilitation program to assess improvements in motor learning and functional recovery [5].
To support these clinical efforts, future preclinical research must align with the Stroke Treatment Academic Industry Roundtable (STAIR) and Stroke Recovery and Rehabilitation Roundtable (SRRR) recommendations. This includes conducting multilaboratory studies, testing during the awake phase of animals, and incorporating aged models with comorbidities [5].
In the realm of pain management, maraviroc holds significant potential as an adjunct therapy. Because it enhances the analgesic effects of opioids, combined administration could allow for reduced therapeutic doses of opioid drugs, thereby minimizing the risk of severe complications, tolerance, and dependence [2]. Finally, further targeted clinical trials are urgently needed to definitively establish the role of CCR5 antagonists in managing severe neuroinflammatory conditions like AIDS-related PML-IRIS [3].
