Anti-Inflammatory and Neuroprotective Effects of Co-UltraPEALut in a Mouse Model of Vascular Dementia

Abstract

Vascular dementia (VaD), the second most common cause of cognitive impairment in the population, is a disease that results from reduction in regional cerebral blood flow and involves oxidative stress and inflammation. Co-ultramicronized PEALut (co-ultra PEALut) is a new compound with beneficial effects, which include anti-inflammatory and antioxidant properties. Recently, co-ultraPEALut has been shown to exhibit neuroprotective effects in models of Parkinson’s disease, cerebral ischemia and Alzheimer’s disease. However, its effects on VaD remain unknown. Therefore, the purpose of the present study was to highlight the potential neuroprotective actions of co-ultraPEALut containing N-palmitoylethanolamine (PEA) and the antioxidant flavonoid luteolin (Lut) (10:1 by mass) in a mouse model of VaD induced by bilateral carotid arteries occlusion. At 24 h after VaD induction, mice were orally treated with 1 mg/kg co-ultraPEALut daily for 15 days. On the 15th day, brain tissues were processed for histological, immunohistochemical, Western blot, and immunofluorescent analysis. Our results clearly demonstrate that co-ultraPEALut improved learning, memory ability, locomotor activity, and the reciprocal social interaction. In addition, the mice subjected to VaD and treated with the co-ultraPEALut showed a reorganization of CA1 and CA3 regions of the hippocampus and restored the number of hippocampal neurons as evidenced by NeuN expression, a specific marker of neurons. Furthermore following carotid arteries ligation, mice treated with co-ultraPEALut showed a modification of proinflammatory, proapoptotic proteins and of oxidative stress as evidenced by the expression of IκB-α, NF-κB p65, Bax, Bcl-2, inducible nitric oxide synthase, and cyclooxygenase-2. In order, co-ultraPEALut treatment restored VaD-induced loss of brain-derived neurotrophic factor and neurotrophins 3 (NT-3) expression in mice. These results confirmed that the neuroprotective effects of co-ultraPEALut were associated with its anti-inflammatory and antioxidant properties.

Oral Ultramicronized Palmitoylethanolamide: Plasma and Tissue Levels and Spinal Anti-hyperalgesic Effect

“…In healthy rats orally administered [ 13 C] 4 -PEA-um, [ 13 C] 4 -PEA was detected in both spinal cord and brain—albeit consistently lower in the former—perhaps a consequence, in part, of the brain's higher perfusion rate compared to spinal cord (Marcus et al, 1977 ). Siracusa et al ( 2017 ) reported a brain level of 21.68 ± 4.67 pmol/g [ 13 C] 4 -PEA 15 min after oral administration of [ 13 C] 4 -PEA-um (30 mg/kg) to healthy rats, in line with our determination of 16.20 ± 6.08 pmol/g. Further, following oral administration of [ 13 C] 4 -PEA-um, levels of [ 13 C] 4 -PEA in spinal cord of CAR rats were 26 to 110-fold higher than in healthy rats, perhaps due to transient changes in the blood-spinal cord-barrier that may occur secondary to CAR-induced peripheral inflammation (Xanthos et al, 2012 ).…”

“…Concerning tissue analysis, prior experience showed high inter-individual variability in plasma levels for a 10 mg/kg dose, especially when using native PEA. Also, published data on blood/tissue levels following PEA administration were performed with higher doses [e.g., 100 mg/kg, Artamonov et al, 2005 ; Vacondio et al, 2015 ]) and 30 mg/kg (Petrosino et al, 2016 ; Siracusa et al, 2017 ). Further, sensitivity of the LC-APCI-MS analysis was a concern.…”

Management of Traumatic Brain Injury: From Present to Future

“…Recent observational clinical studies reported the beneficial use of ultramicronized PEA as an add-on therapy in patients suffering from low back pain [103] as well as in patients suffering from fibromyalgia syndrome (FMS) [104]. In addition, interestingly, a co-ultramicronized PEA/luteolin (PEALUT) composite (10:1 mass ratio) displayed important neuroprotective effects in preclinical studies for various conditions (e.g., TBI, arthritis, depression, neurogenesis, Parkinson's and Alzheimer's diseases, and spinal cord injury) and, more recently, in experimental models of autism and vascular dementia [105][106][107][108][109][110][111][112][113]. In addition, Caltagirone et al [114] showed that co-ultra PEALUT reduced brain injury in a rat model of Middle Cerebral Artery Occlusion (MCAO) and, more interestingly, in a clinical study.…”

Tanshinone IIA Alleviates CCL2-Induced Leaning memory and Cognition Impairment in Rats: A Potential Therapeutic Approach for HIV-Associated Neurocognitive Disorder

“…Although the exact mechanism of HAND is unknown, many studies have shown that the high incidence of cognitive impairment is due to oxidative stress and inflammation [15], each of which plays an important role in the development of cognitive impairment. It has been reported that oxidative stress induces oxidative damage through apoptotic and inflammatory factors leading to cell death and to learning, memory, and cognitive impairments [16]. Indeed, our recent study showed that intrahippocampal injection of CCL2 impaired learning memory and cognition in rats via apoptosis of hippocampal neurons [17], and rats with CCL2-induced cognitive disorder could be used as an ideal murine model to study the effect of CCL2 on HAND.…”