Roflumilast promotes memory recovery and attenuates white matter injury in aged rats subjected to chronic cerebral hypoperfusion

Abstract

Chronic cerebral hypoperfusion (CCH) has been associated with aging-related vascular dementia, including Alzheimer's disease. It can be induced by the four-vessel occlusion/internal carotid artery (4VO/ICA) model in aged rats, resulting in persistent memory deficits, white matter injury, and significant neuronal loss in the hippocampus and cerebral cortex. The phosphodiesterase type 4 inhibitor (PDE4-I) roflumilast has been reported to have pro-cognitive effects in several behavioral paradigms. The present study evaluated the effects of repeated roflumilast treatment in aged rats that were subjected to CCH. After surgery, roflumilast (0.003 and 0.01 mg/kg) was administered intraperitoneally once per day for 29 days. Memory performance was assessed in the aversive radial maze (AvRM) 7, 14, and 21 days after CCH. The effects of roflumilast on hippocampal neurodegeneration and white matter injury were investigated using Nissl and Kluver-Barrera staining, respectively. Western blot and RT-qPCR were used to explore microglial polarization using M1 (Iba-1 and iNOS) and M2 (Arginase-1) markers. Chronic cerebral hypoperfusion caused persistent memory deficits, hippocampal neurodegeneration, and vacuolization and fiber disarrangement in white matter. Repeated roflumilast treatment restored CCH-induced cognitive impairments in aged rats but in the absence of the rescue of hippocampal neurons. Attenuation of white matter injury was detected in the optic tract in aged CCH rats that were treated with roflumilast. In vitro, roflumilast increased Arg-1 gene expression in myelin-laden primary microglia. The present data suggest that roflumilast might be useful for the treatment of cognitive sequelae associated with CCH.

Adenosine A2A Receptors in Bone Marrow-Derived Cells Attenuate Cognitive Impairment in Mice After Chronic Hypoperfusion White Matter Injury

“…Chronic hypoperfusion is an important factor leading to vascular cognitive impairment, and it has received increasing attention in recent years. The phosphodiesterase inhibitor roflumilast [24] and the transient receptor potential melastatin 2 (TRPM2) inhibitor [25] can suppress microglial activity after CCH injury and promote cognitive function recovery through anti-inflammatory effects. IL-1β receptor inhibitors and IL-1β knockout mice block the IL-1β signaling pathway, thereby inducing oligodendrocyte premature cell migration to the periphery of the corpus callosum, and avoiding white matter damage and reversing chronic hypoperfusion-induced cognitive dysfunction by improving the local inflammatory environment [26].…”

Baicalin ameliorates neuroinflammation-induced depressive-like behavior through inhibition of toll-like receptor 4 expression via the PI3K/AKT/FoxO1 pathway

“…For Nissl staining [49], the brain slices were dewaxed with xylene and hydrated in a graded series of alcohol. Then, the samples were stained by a Nissl solution for 10 min, washed with distilled water, dehydrated by gradient alcohol, transparentized by xylene, and mounted by neutral balsam.…”

Tripchlorolide May Improve Spatial Cognition Dysfunction and Synaptic Plasticity after Chronic Cerebral Hypoperfusion

“…Previous studies have shown that CCH exacerbates neurodegeneration via multiple mechanisms, including the induction of oxidative stress which involves fatty acids, proteins, DNA, and mitochondria, blood-brain barrier disruption, increases in neuronal Ca 2+ [5], A β accumulation and aggravation [6], tau hyperphosphorylation, synaptic dysfunction, neuronal loss, white matter lesions, release of neuroinflammatory cytokines [7–9], excessive autophagy [10], and overactivation of microglia in the hippocampus [11, 12]. These events lead to mitochondrial dysfunction via activation of mitophagy, changes in mitochondrial morphology due to imbalance in fusion and fission events [10, 13, 14], disturbances in lipid metabolism [15], disruption of the integrity of the white matter and fiber disarrangement of the white matter [16, 17], alterations in growth factor expression [15], inhibition of neurogenesis [18], and neurotransmitter system dysfunction [2]. Furthermore, CCH can lead to the downregulation of synaptic proteins and demyelination and the reduction of dendritic spines in the hippocampus, which then leads to a reduction in synaptic transmission and neuroplasticity [12, 19, 20].…”