ABSTRACT
AIMS: With a focus on the discrepancy between preclinical and clinical findings, this review will gather comprehensive information about the effects of calcineurin inhibitors (CNI) on cognitive function and related brain pathology from in vitro, in vivo, and clinical studies. We also summarize the potential mechanisms that underlie the pathways related to CNI-induced cognitive impairment. METHODS: We systematically searched articles in PubMed using keywords 'calcineurin inhibitor*' and 'cognition' to identify related articles, which the final list pertaining to underlying mechanisms of CNI on cognition. RESULTS: Several studies have reported an association between calcineurin and the neuropathology of Alzheimer's disease (AD). AD is the most common neurocognitive disorder associated with amyloid plaques and neurofibrillary tangles in the brain, leading to cognitive impairment. CNI, including tacrolimus and cyclosporin A, are commonly prescribed for patients with transplantation of solid organs such as kidney, liver, or heart, those drugs are currently being used as long-term immunosuppressive therapy. Although preclinical models emphasize the favorable effects of CNI on the restoration of brain pathology due to the impacts of calcineurin on the alleviation of amyloid-beta deposition and tau hyperphosphorylation, or rescuing synaptic and mitochondrial functions, treatment-related neurotoxicity, resulting in cognitive dysfunctions has been observed in clinical settings of patients who received CNI. CONCLUSION: Inconsistent results of CNI on cognition from clinical studies have been observed due to impairment of the blood-brain barrier, neuroinflammation mediated by reactive oxygen species, and alteration in mitochondrial fission, and extended research is required to confirm its promising use in cognitive impairment.
Subject(s)
Calcineurin Inhibitors , Cognition , Humans , Calcineurin Inhibitors/pharmacology , Calcineurin Inhibitors/therapeutic use , Calcineurin Inhibitors/adverse effects , Animals , Cognition/drug effects , Cognitive Dysfunction/drug therapy , Cognitive Dysfunction/metabolism , Brain/drug effects , Brain/metabolism , Calcineurin/metabolism , Alzheimer Disease/metabolism , Alzheimer Disease/drug therapy , Immunosuppressive Agents/pharmacology , Immunosuppressive Agents/therapeutic use , Immunosuppressive Agents/adverse effectsABSTRACT
Middle cerebral artery occlusion (MCAO) causes focal cerebral hypoperfusion, resulting in cerebral ischemia or ischemic stroke. The main therapeutic approach is to restore an adequate blood flow to the brain via the process of reperfusion. However, rapid reperfusion can itself aggravate brain damage; this adverse effect is known as ischemic/reperfusion (I/R) injury. The pathological conditions that occur after cerebral ischemia and cerebral I/R are microvascular injury, blood-brain barrier dysfunction, post-ischemic inflammation, increased oxidative stress/reactive oxygen species, and a reduction in neuronal survival, leading to brain infarction. Animal and clinical studies on hyperbaric oxygen therapy (HBOT) have recently been carried out, and there is evidence of positive effects on neurological outcomes after cerebral ischemia. However, some evidence has shown that HBOT may not affect the functional recovery after ischemic injury. This review describes the current evidence, both in vivo and clinical data, regarding the potential benefits of HBOT after MCAO and cerebral I/R injury. The contrary data are also discussed to verify the effectiveness of HBOT in stroke outcomes.
