Sphingosine‐1‐phosphate receptor modulators in stroke treatment

Abstract

Globally, stroke is a primary reason for death and lasting disability (Benjamin et al., 2019). Inflammation is critical in the course of a stroke and is closely linked to prognosis (Anrather & Iadecola, 2016).The inflammatory response following stroke involves immune cell infiltration, glial cell activation, and the emission of diverse neurotoxic molecules, such as pro-inflammatory cytokines, matrix metalloproteinases, and nitric oxide synthase, which further exacerbates neurological damage by causing endothelial cell damage, bloodbrain barrier (BBB) disruption, and neuronal apoptosis (Jayaraj et al., 2019). Therefore, immunotherapy targeting the post-stroke

Beneficial Effect of Fingolimod in a Lafora Disease Mouse Model by Preventing Reactive Astrogliosis-Derived Neuroinflammation and Brain Infiltration of T-lymphocytes

“…At the level of the central nervous system (CNS), modulators (antagonists) of S1PR1 signaling, like fingolimod, have specific actions on every CNS cell type: (i) in endothelial cells, by reducing the permeability of the blood–brain barrier (BBB), decreasing expression of ICAM-1, and reducing the binding of leukocytes to endothelial cells; (ii) in neurons, by preventing apoptosis and protecting from excitotoxic death; (iii) in astrocytes, by inhibiting the production of proinflammatory cytokines, chemokines, and neurotoxic substances (e.g., IL-6, COX2, VEGF), by increasing the production of neuroprotective factors and by preventing the activation and proliferation of astrocytes; (iv) in microglia, by reducing microglia activation, reducing the production of proinflammatory cytokines (IL-6), and by promoting polarization to M2 phenotype; (v) in oligodendrocytes, by promoting the renewal of oligodendrocytes and enhancing remyelination. In conclusion, fingolimod reduces inflammation, excitotoxicity, glial activation and polarization, and BBB destruction, and improves neurogenesis [ 42 ]. For all these reasons, fingolimod has a beneficial effect on different neurological disorders such as stroke [ 42 ], hypoxia [ 43 ], and epilepsy [ 44 – 47 ].…”

“…In conclusion, fingolimod reduces inflammation, excitotoxicity, glial activation and polarization, and BBB destruction, and improves neurogenesis [ 42 ]. For all these reasons, fingolimod has a beneficial effect on different neurological disorders such as stroke [ 42 ], hypoxia [ 43 ], and epilepsy [ 44 – 47 ].…”

Beneficial effect of fingolimod in a Lafora disease mouse model by preventing reactive astrogliosis-derived neuroinflammation and brain infiltration of T-lymphocytes.

“…At the level of the central nervous system (CNS), modulators (antagonists) of S1PR1 signaling, like ngolimod, have speci c actions on every CNS cell type: i) in endothelial cells, by reducing the permeability of the blood-brain barrier (BBB), decreasing expression of ICAM-1, and reducing the binding of leukocytes to endothelial cells; ii) in neurons, by preventing apoptosis and protecting from excitotoxic death; iii) in astrocytes, by inhibiting the production of proin ammatory cytokines, chemokines and neurotoxic substances (e.g., IL-6, COX2, VEGF), by increasing the production of neuroprotective factors and by preventing the activation and proliferation of astrocytes; iv) in microglia, by reducing microglia activation, reducing the production of proin ammatory cytokines (IL-6), and by promoting polarization to M2 phenotype; v) in oligodendrocytes, by promoting the renewal of oligodendrocytes and enhancing remyelination. In conclusion, ngolimod reduces in ammation, excitotoxicity, glial activation and polarization, and BBB destruction, and improves neurogenesis [42]. For all these reasons, ngolimod has a bene cial effect on different neurological disorders such as stroke [42], hypoxia [43], and epilepsy [44], [45], [46], [47].…”

“…In conclusion, ngolimod reduces in ammation, excitotoxicity, glial activation and polarization, and BBB destruction, and improves neurogenesis [42]. For all these reasons, ngolimod has a bene cial effect on different neurological disorders such as stroke [42], hypoxia [43], and epilepsy [44], [45], [46], [47].…”

Development of Scalable Processes for the Preparation of 4-(chloromethyl)-1-cyclohexyl-2-(trifluoromethyl)benzene: A Key Intermediate for Siponimod

“…Through subsequent hydrogenation, reduction, and substitution steps, benzyl bromide 8 was obtained as the key intermediate for further transformations. Although the total yield was not explicitly mentioned in the Novartis’ patents, previous studies in 2017 reported a yield of 63.7% over four steps using similar approaches . Despite the concise nature of the coupling methodologies, the expensive starting materials (>$1300/kg according to Scifinder n ) and the requirement for noble-metal catalysts posed challenges in terms of budget control during process development.…”