Cortistatin (CST) is a cyclic-neuropeptide produced by brain cortex and immune cells that shows immunomodulatory and neuroprotective effects in cell-based systems and pre-clinical models of ischaemia, excitotoxicity, and bacterial meningoencephalitis. Recently, we have identified that CST provides a highly effective therapy for the pre-clinical models of multiple sclerosis (experimental autoimmune encephalomyelitis, EAE model) and Parkinson´s disease (PD). In EAE, CST reduced the two deleterious components of the disease, the autoimmune and inflammatory responses. In addition, CST modulated the demyelinating processes by regulating gliosis and mounting an active program of neuroprotection. We showed that CST deactivated the inflammatory response of resident glial cells, but, at the same time, it induced their CNS supporting roles keeping intact the phagocytosis and trophic functions of these cells. Following this, we also explore whether CST provides benefit in the MPTP-induced pre-clinical model of PD (that recapitulate human pathology). Our results demonstrated that treatment with CST avoided MPTP-induced deficits in locomotor activity, protected from dopaminergic-related toxicity in the striatum and substantia nigra, and reduced neuroinflammation by regulating microglial and astrocyte activation. Interestingly, while cortistatin-deficient mice were partially resistant to EAE, they showed an increased susceptibility to MPTP. Using glial cells isolated from CST-deficient mice, we demonstrated that lack of CST induced an activated phenotype in microglia and astrocytes, which showed exacerbated and dysregulated responses to inflammatory stimulation. Of note, CST levels are significantly decreased in the CNS of animals with experimental autoimmune encephalomyelitis, in the temporal lobe of Alzheimer´s patients, and in the retina of diabetic patients (in which low amounts of CST correlated to increased retinal neurodegeneration and glial activation). Together, these results support the potential of CST in modulating neurodegeneration in an inflammatory milieu, combining the downregulation of neuroinflammation with trophic support and neuroprotection. Moreover, our findings suggest a crucial role for endogenous CST as a normalizing factor for the glial niche.