Intranasal Dexamethasone Reduces Mortality and Brain Damage in a Mouse Experimental Ischemic Stroke Model

Abstract

Neuroinflammation triggered by the expression of damaged-associated molecular patterns released from dying cells plays a critical role in the pathogenesis of ischemic stroke. However, the benefits from the control of neuroinflammation in the clinical outcome have not been established. In this study, the effectiveness of intranasal, a highly efficient route to reach the central nervous system, and intraperitoneal dexamethasone administration in the treatment of neuroinflammation was evaluated in a 60min middle cerebral artery occlusion (MCAO) model in C57BL/6 male mice. We performed a side-by-side comparison using intranasal versus intraperitoneal dexamethasone, a timecourse including immediate (0 h) or 4 or 12 h poststroke intranasal administration, as well as 4 intranasal doses of dexamethasone beginning 12 h after the MCAO versus a single dose at 12 h to identify the most effective conditions to treat neuroinflammation in MCAO mice. The best results were obtained 12 h after MCAO and when mice received a single dose of dexamethasone (0.25 mg/kg) intranasally. This treatment significantly reduced mortality, neurological deficits, infarct volume size, blood-brain barrier permeability in the somatosensory cortex, inflammatory cell infiltration, and glial activation. Our results demonstrate that a single low dose of intranasal dexamethasone has neuroprotective therapeutic effects in the MCAO model, showing a better clinical outcome than the intraperitoneal administration. Based on these results, we propose a new therapeutic approach for the treatment of the damage process that accompanies ischemic stroke.

The Therapeutic Effect of Intranasal Administration of Dexamethasone in Neuroinflammation Induced by Experimental Pulmonary Tuberculosis

“…Similar results have been observed in a 60-min middle cerebral artery occlusion stroke model. IN DEX reduced strikingly the ischemic brain tissue damage, reduced blood-brain barrier permeability, decreased mortality and improved the Neurological deficit (7-point neuroscore scale) and weight of animals [ 14 ]. Another study showed that intranasal administration of methylprednisolone to mice with experimental autoimmune encephalomyelitis (EAE) suppressed the neuroinflammatory response and reduced immune cell infiltration and demyelination, in a similarly way to intravenous administration [ 36 ].…”

“…Their therapeutic value is enormous in a wide range of autoimmune/inflammatory diseases, and GCs have been widely used for treating autoimmune disorders, allergies, allograft rejection, neuroinflammation, and neoplastic diseases [ 10 ]. In this context, DEX, a potent anti-inflammatory synthetic GC, has been used to reduce inflammation in different neuroinflammatory conditions [ 14 , 17 , 37 ]. In the present study, we showed that treatment with L/DEX (0.05 mg/kg BW) and M/DEX (0.25 mg/kg BW) through the IN route in the murine pulmonary TB model significantly decreased neuroinflammation, improving behavioral status without aggravating lung disease.…”

“…These abnormal activities are produced by brain inflammation, which induces depression by diverse pathophysiological processes, such as disturbing monoaminergic neurotransmission, induce oxidative injury, and hippocampal neuronal damage. Indeed, DEX has been used to reduce inflammation in diverse neuroinflammatory conditions [ 14 , 17 ]. Different studies demonstrated that the anti-inflammatory effects of glucocorticoids such as DEX were attributable to the reduced expression of IL1β, IL2, TGFβ, and TNFα [ 42 ].…”

“…Dexamethasone (DEX) is a synthetic glucocorticoid steroidal anti-inflammatory agent able to attenuate the early expression of pro-inflammatory cytokines produced by activated microglia/macrophages [ 12 ]. GCs are administered intravenously, intramuscularly, or orally, all routes that require high doses to achieve a therapeutic concentration within the CNS, with several adverse side effects, such as diabetes, glaucoma, and osteoporosis when patients receive high doses systemically or over a long time [ 13 , 14 ]. Inhaled GCs (IGCs) have less oral bioavailability and a greater lipophilicity, thus a greater efficacy with fewer side effects, furthermore IGCs are the most effective treatment in asthma because they control symptoms and prevent exacerbations [ 15 ].…”

“…Therefore, a treatment strategy to reduce these systemic side effects is necessary. Intranasal delivery (IN) has been shown to give a route to direct drug transport along the olfactory and trigeminal nerves, allowing brain access for small and large molecules, and even stem cells in therapeutic concentrations, avoiding the side effects of systemic administration [ 14 , 17 , 18 ].…”