Neurodegenerative disorders encompass a broad spectrum of profoundly disabling situations that impact millions of individuals globally. While their underlying causes and pathophysiology display considerable diversity and remain incompletely understood, a mounting body of evidence indicates that the disruption of blood-brain barrier (BBB) permeability, resulting in brain damage and neuroinflammation, is a common feature among them. Consequently, targeting the BBB has emerged as an innovative therapeutic strategy for addressing neurological disorders. Within this review, we not only explore the neuroprotective, neurotrophic, and immunomodulatory benefits of mesenchymal stem cells (MSCs) in combating neurodegeneration but also delve into their recent role in modulating the BBB. We will investigate the cellular and molecular mechanisms through which MSC treatment impacts primary age-related neurological conditions like Alzheimer’s disease, Parkinson’s disease, and stroke, as well as immune-mediated diseases such as multiple sclerosis. Our focus will center on how MSCs participate in the modulation of cell transporters, matrix remodeling, stabilization of cell-junction components, and restoration of BBB network integrity in these pathological contexts.

Parkinson’s disease (PD) is a complex disorder characterized by the impairment of the dopaminergic nigrostriatal system. PD has duplicated its global burden in the last few years, becoming the leading neurological disability worldwide. Therefore, there is an urgent need to develop innovative approaches that target multifactorial underlying causes to potentially prevent or limit disease progression. Accumulating evidence suggests that neuroinflammatory responses may play a pivotal role in the neurodegenerative processes that occur during the development of PD. Cortistatin is a neuropeptide that has shown potent anti-inflammatory and immunoregulatory effects in preclinical models of autoimmune and neuroinflammatory disorders. The goal of this study was to explore the therapeutic potential of cortistatin in a well-established preclinical mouse model of PD induced by acute exposure to the neurotoxin 1-methil-4-phenyl1-1,2,3,6-tetrahydropyridine (MPTP). We observed that treatment with cortistatin mitigated the MPTP-induced loss of dopaminergic neurons in the substantia nigra and their connections to the striatum. Consequently, cortistatin administration improved the locomotor activity of animals intoxicated with MPTP. In addition, cortistatin diminished the presence and activation of glial cells in the affected brain regions of MPTP-treated mice, reduced the production of immune mediators, and promoted the expression of neurotrophic factors in the striatum. In an in vitro model of PD, treatment with cortistatin also demonstrated a reduction in the cell death of dopaminergic neurons that were exposed to the neurotoxin. Taken together, these findings suggest that cortistatin could emerge as a promising new therapeutic agent that combines anti-inflammatory and neuroprotective properties to regulate the progression of PD at multiple levels.

Neurodegenerative diseases encompass a broad spectrum of profoundly disabling disorders that impact millions of individuals globally. While their underlying causes and pathophysiol-ogy display considerable diversity and remain incompletely understood, a mounting body of evidence indicates that the disruption of blood-brain barrier (BBB) permeability, resulting in brain damage and neuroinflammation, constitutes a shared characteristic among them. Con-sequently, targeting the BBB has emerged as an innovative therapeutic strategy for address-ing neurological diseases. Within this review, we not only explore the neuroprotective, neu-rotrophic, and immunomodulatory benefits of mesenchymal stem cells (MSCs) in combating neurodegeneration but also delve into their recent role in modulating the BBB. We will delve into the cellular and molecular mechanisms through which MSC treatment impacts primary age-related neurological disorders like Alzheimer’s disease, Parkinson’s disease, and stroke as well as immune-mediated conditions such as multiple sclerosis. Our focus will center on how MSCs participate in the modulation of cell transporters, matrix remodeling, stabilization of cell-junction components, and restoration of BBB network integrity in these pathological con-texts.

Background: Ischemic stroke remains a leading cause of death and disability, with limited therapies addressing its pathophysiology. Neuroinflammation, blood–brain barrier disruption, and immune dysregulation critically contribute to both acute neuronal injury and chronic functional decline. Elucidating the endogenous factors that govern these processes and understanding the intricate interplay among them is essential for developing effective therapeutic strategies. Cortistatin, a neuropeptide expressed in the nervous and immune systems, exhibits potent immunomodulatory actions, but its role in neuroinflammatory diseases remains unclear. Methods: In this study, we combined human and murine transcriptomic analyses with a preclinical stroke model in cortistatin-deficient mice to investigate the endogenous and therapeutic roles of cortistatin during the acute (48 h) and subacute (7 days) phases of ischemic stroke. Results: We demonstrate for the first time that cortistatin deficiency amplified ischemia-induced transcriptional programs, heightening neuroinflammation and glial/neurovascular dysfunction, and worsening neurological outcomes. Interestingly, cortistatin deficiency accelerated aging-associated pathological features, underscoring its essential role in neuroimmune and cerebrovascular homeostasis. Conversely, cortistatin administration improved neuronal survival, mitigated immune dysfunction, and preserved myelin and vascular integrity during both the acute and subacute stages. Conclusions: These findings provide the first evidence identifying cortistatin as an endogenous neuroimmune regulator in ischemic stroke and a promising multimodal therapeutic agent for improving acute and long-term outcomes. Trial registration: Not applicable

Ischemic stroke is the result of a permanent or transient occlusion of a brain artery, leading to irreversible tissue injury and long-term sequelae. Despite ongoing improvements, therapeutic failure remains notorious, and stroke remains the second leading cause of death worldwide. Neuroinflammation, blood-brain barrier (BBB) breakdown, and immune deregulation are the major hallmarks of the pathogenesis and outcomes of brain ischemia. Understanding the interconnected and complex mechanisms and the endogenous mediators that globally modulate these responses is essential for developing successful therapeutic strategies. In this context, our study focuses on cortistatin, a neuropeptide widely distributed in the central nervous and immune systems. The anti-inflammatory, immunomodulatory, and neuroprotective properties of cortistatin make it an attractive novel therapeutic agent against ischemic stroke. To this aim, we evaluated the potential effect of cortistatin in the widely-known preclinical model of stroke MCAO (middle cerebral artery occlusion) in young (3 months old) and middle-aged (6 months old) wild-type mice. We observed that late treatment with cortistatin (24 h after stroke) improved neurological score, induced smaller lesions, reduced/modulated glial response, astrocytic scar formation and BBB recovery, and decreased peripheral immune activity. This beneficial effect of cortistatin suggests that multimodal-based therapies may represent a novel treatment for ischemic stroke, holding great promise compared to interventions targeting only a single aspect of stroke pathophysiology. Moreover, we found that the absence of cortistatin in young and middle-aged cortistatin-deficient animals increased susceptibility to stroke and worsened prognosis (i.e., severe neurological score, altered microglial response, impaired astrocyte scar, disrupted BBB, dysregulated angiogenesis, and exacerbated immune infiltration and peripheral response). Interestingly, cortistatin treatment reversed stroke outcomes in animals lacking this neuropeptide, which highlights the key role of cortistatin in regulating the intricate interplay between the nervous and the immune systems, modulating dysregulated cellular and molecular responses from both systems that could impact brain homeostasis. Together, our findings underscore the relevance of identifying the endogenous and therapeutic role of neuro-immune mediators underlying ischemic stroke, and emphasize the critical need to consider multifactorial therapeutic approaches administered at later times and across different ages and phenotypes to extend the current therapeutic window for most patients who do not meet the clinical criteria.