Abstract-The ability of the central nervous system to cope with stressful conditions was shown to be dependent on proper T-cell-mediated immune response. Because the therapeutic window for neuroprotection after acute insults such as stroke is relatively narrow, we searched for a procedure that would allow the relevant T cells to be recruited rapidly. Permanent middle cerebral artery occlusion was induced in adult rats. To facilitate a rapid poststroke T cell activity, rats were treated with poly-YE using different regimens. Control and poly-YE-treated rats were assessed for functional recovery using neurological severity score and Morris water maze. Neuroprotection, neurogenesis, growth factor expression, and microglial phenotype were assessed using histological and immunofluorescence methods. Administration of poly-YE as late as 24 hours after middle cerebral artery occlusion yielded a beneficial effect manifested by better neurological performance, reduced neuronal loss, attenuation of behavioral deficits, and increased hippocampal and cortical neurogenesis. This compound affected the subacute phase by modulating microglial response and by increasing local production of insulin-like growth factor-I, known to be a key player in neuronal survival and neurogenesis. The relative wide therapeutic window, coupled with its efficacy in attenuating further degeneration and enhancing restoration, makes poly-YE a promising immune-based candidate for stroke therapy. Key Words: neuroprotection Ⅲ neurogenesis Ⅲ reactive microglia Ⅲ stroke P reviously, we have demonstrated that central nervous system (CNS) trauma spontaneously evokes a beneficial, T-cell-mediated immune response, which reduces neuronal loss. 1 In the damaged CNS tissue, CNS-specific T cells accumulate and become reactivated on recognizing and interacting with their corresponding autoantigens presented to them by local antigen-presenting cells. 2,3 This in turn leads to the production of specific neurotrophic factors (eg, brainderived neurotrophic factor) by T cells, and to the proper activation of microglia/macrophages. 4,5 Enhancing the activity of CNS-specific T cells (by a well-regulated passive or active immunization) was found to be beneficial in various animal models of CNS injuries. 6 -8 The ability to maintain autoimmunity in healthy individuals, without developing autoimmune disease, was shown to be regulated by naturally occurring CD4 ϩ CD25 ϩ regulatory T cells. However, recovery from CNS injury can benefit from a transient elimination or decreased activity of these cells. 9 Compounds that can downregulate the constitutive suppression of regulatory T cells (Treg) were therefore considered by us as potential candidates.We found that poly-YE, a high-molecular-weight (22 to 45 kDa) copolymer that was shown to exert modulatory effects on the immune system, 10,11 is capable of downregulating the activity of the regulatory T cells, and used this copolymer to facilitate the spontaneous response of effector T cells recognizing antigens associated with a ...
ObjectiveLadostigil reduces oxidative stress and microglial activation in aging rats. We assessed its safety and potential efficacy in a 3-year, randomized, double-blind, placebo-controlled phase 2 clinical trial in patients with mild cognitive impairment (MCI) and medial temporal lobe atrophy.MethodsPatients 55 to 85 years of age with MCI, Clinical Dementia Rating (CDR) score of 0.5, Mini-Mental State Examination (MMSE) score >24, Wechsler Memory Scale–Revised Verbal Paired Associates I score ≤18, and Medial Temporal Lobe Atrophy Scale score >1 were stratified by APOE ε4 genotype and randomly assigned (1:1) to ladostigil 10 mg/d or placebo. Primary outcomes were safety and onset of Alzheimer disease dementia. Secondary endpoints were Neuropsychological Test Battery (NTB) composite, Disability Assessment in Dementia (DAD), and Geriatric Depression Scale (GDS) scores. Exploratory outcomes were NTB component, CDR, and MMSE scores. Biomarkers included MRI-derived whole-brain, hippocampus, and entorhinal cortex volumes.ResultsTwo hundred ten patients from 15 sites in Austria, Germany, and Israel were randomly allocated to placebo (107 patients) or ladostigil (103 patients). After 36 months, 21 of 103 patients on placebo and 14 of 99 patients receiving ladostigil progressed to Alzheimer disease (log-rank test p = 0.162). There were no significant effects on the NTB composite, DAD, or GDS score. Whole-brain and hippocampus volumes decreased more in the placebo than in the ladostigil group (whole brain, p = 0.025, Cohen d = 0.43; hippocampus, p = 0.043, d = 0.43). Serious adverse events were reported by 28 of 107 patients treated with placebo and 26 of 103 with ladostigil.ConclusionLadostigil was safe and well tolerated but did not delay progression to dementia. Its association with reduced brain and hippocampus volume loss suggests a potential effect on atrophy.ClinicalTrials.gov identifierNCT 01429623.Classification of evidenceThis study provides Class II evidence that for patients with MCI and medial temporal lobe atrophy, ladostigil did not significantly decrease the risk of the development of Alzheimer disease.
ClinicalTrials.gov identifier: NCT00567710.
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