Palmitoylethanolamide exerts neuroprotective effects in mixed neuroglial cultures and organotypic hippocampal slices via peroxisome proliferator-activated receptor-α

<p>Abstract</p> <p>Background</p> <p>In addition to cytotoxic mechanisms directly impacting neurons, β-amyloid (Aβ)-induced glial activation also promotes release of proinflammatory molecules that may self-perpetuate reactive gliosis and damage neighbouring neurons, thus amplifying neuropathological lesions occurring in Alzheimer's disease (AD). Palmitoylethanolamide (PEA) has been studied extensively for its anti-inflammatory, analgesic, antiepileptic and neuroprotective effects. PEA is a lipid messenger isolated from mammalian and vegetable tissues that mimics several endocannabinoid-driven actions, even though it does not bind to cannabinoid receptors. Some of its pharmacological properties are considered to be dependent on the expression of peroxisome proliferator-activated receptors-α (PPARα).</p> <p>Findings</p> <p>In the present study, we evaluated the effect of PEA on astrocyte activation and neuronal loss in models of Aβ neurotoxicity. To this purpose, primary rat mixed neuroglial co-cultures and organotypic hippocampal slices were challenged with Aβ_1-42and treated with PEA in the presence or absence of MK886 or GW9662, which are selective PPARα and PPARγ antagonists, respectively. The results indicate that PEA is able to blunt Aβ-induced astrocyte activation and, subsequently, to improve neuronal survival through selective PPARα activation. The data from organotypic cultures confirm that PEA anti-inflammatory properties implicate PPARα mediation and reveal that the reduction of reactive gliosis subsequently induces a marked rebound neuroprotective effect on neurons.</p> <p>Conclusions</p> <p>In line with our previous observations, the results of this study show that PEA treatment results in decreased numbers of infiltrating astrocytes during Aβ challenge, resulting in significant neuroprotection. PEA could thus represent a promising pharmacological tool because it is able to reduce Aβ-evoked neuroinflammation and attenuate its neurodegenerative consequences.</p

Cannabidiol Reduces Aβ-Induced Neuroinflammation and Promotes Hippocampal Neurogenesis through PPARγ Involvement

Peroxisome proliferator-activated receptor-γ (PPARγ) has been reported to be involved in the etiology of pathological features of Alzheimer's disease (AD). Cannabidiol (CBD), a Cannabis derivative devoid of psychomimetic effects, has attracted much attention because of its promising neuroprotective properties in rat AD models, even though the mechanism responsible for such actions remains unknown. This study was aimed at exploring whether CBD effects could be subordinate to its activity at PPARγ, which has been recently indicated as its putative binding site. CBD actions on β-amyloid-induced neurotoxicity in rat AD models, either in presence or absence of PPAR antagonists were investigated. Results showed that the blockade of PPARγ was able to significantly blunt CBD effects on reactive gliosis and subsequently on neuronal damage. Moreover, due to its interaction at PPARγ, CBD was observed to stimulate hippocampal neurogenesis. All these findings report the inescapable role of this receptor in mediating CBD actions, here reported

The roles of carbon monoxide and nitric oxide in the control of the neuroendocrine stress axis:complementary or redundant

There is widespread evidence in favour of nitric oxide (NO) acting as a gaseous neurotransmitter in the central nervous system, diffusing from its cells of origin and affecting surrounding neuronal tissue in evanescent three-dimensional waves. This is also true of the hypothalamus, where amongst other activities NO inhibits stimulation of corticotrophin-releasing hormone (CRH) and vasopressin release by inflammatory stressors, effects thought to be mediated by binding with soluble guanylate cyclase (sGC). Carbon monoxide is being increasingly recognised as another gaseous neuromodulator, but with principal effects on other hemoproteins such as cyclo-oxygenase, and a distinctly different profile of localisation.NO is predominantly a pro-inflammatory agent in the periphery while CO is often anti-inflammatory. In the hypothalamus, the actions of CO are also distinct from those of NO,with marked antagonistic effects on the inflammatory release of vasopressin, both in vitro and in vivo, but with little involvement in the regulation of CRH. Thus, it would appear that these apparently similar gases exert quite distinct and separate effects, although they cause broadly similar overall changes in the secretion of neuroendocrine stress hormones. We conclude that these two gases may play significant but different roles in the control of the neuroendocrine stress response, but one common feature may be attenuation of inflammation-induced release of stress hormones

Primary cultures of microglial cells for testing toxicity of anticancer drugs

Toxicity of anticancer agents on normal neural cells during chemotherapy of primary or secondary brain tumors is a clinical problem of increasing relevance and concern. In this perspective, here we used primary cultures of rat cortical microglia as an in vitro paradigm of normal glia to investigate the neurotoxicity of anticancer agents. The effects of two compounds frequently used for treatment of brain tumors, methotrexate (MTX) and temozolomide (TMZ), were compared to those of a known microglial activator, bacterial lipopolysaccharide (LPS); cell viability and metabolism was assessed by the MTS assay. We found that LPS, in the low-intermediate range of concentrations, strongly activates microglia cells, but a highly significant decrease in viability was observed from 100 ng/ml onward. TMZ has no effect at concentrations of clinical interest, whereas MTX significantly increases cell metabolism at 30 muM, a phenomenon possibly reflecting MTX neurotoxicity observed in patients. (C) 2004 Elsevier Ireland Ltd. All rights reserved

Valproic acid inhibits proliferation and affects androgen sensitivity in prostatic cancer cells.

Valproic acid (VA), a drug used as an anticonvulsant and mood stabilizer, has been shown to impair cell growth and evoke cell differentiation in several cell types. In the present study, we investigated the effect of VA on the proliferation of both androgen-sensitive (LNCaP) and -insensitive (PC-3) prostate cancer cells. Moreover, we explored the effect of VA on the androgen response of these two models with the aim of establishing whether the drug modulates or induces hormone sensitivity. LNCaP cells were plated at a density of 50,000 cells/ml in RPMI 1640 supplemented with 10% foetal bovine serum (FBS) in 60-mm plastic Petri dishes. Forty-eight h later, the medium was changed with RPMI 1640 supplemented with 5% charcoal-treated FBS (CH-FBS) containing VA (75 Ìg/ml). PC-3 cells were plated at a density of 25,000 cells/ml in Dulbecco Modified Eagle’s Medium (DMEM) supplemented with 5% FBS in 60-mm plastic Petri dishes. Twenty-four h later, the medium was changed with DMEM supplemented with 5% CH-FBS containing VA (75 Ìg/ml). The medium with the drug was renewed every 48 h and cell counts performed after 2, 4 and 6 days of treatment. In experiments performed to evaluate the effect of VA on the androgen sensitivity of LNCaP cells, these cells were pretreated for 48h with VA (75 Ìg/ml) and subsequently exposed to dihydrotestosterone (DHT) at concentrations ranging from 10-11 to 10-5 M. Alternatively, cells were treated with VA combined with the above mentioned DHT concentrations. PC-3 cells were also exposed to VA associated with DHT (10-10, 10-9 and 10-8 M). Our data indicate that VA induced a slight inhibition of LNCaP cell proliferation (about 15% with respect to control). Nevertheless, when used in the sequential modality or in combination with 10-10-10-7 M DHT, it strongly reduced or suppressed the androgenpromoted cell growth. In addition, it generally amplified the inhibitory effect provoked by 10-6-10-5 M DHT. PC-3 cell proliferation was markedly reduced by VA, the maximum inhibition reaching 40% when compared to control. When DHT, which is ineffective on PC-3 cell growth when used alone, was combined with VA, it was able to counteract the inhibitory action of VA, inducing a slight stimulation of cell growth at 10-9 and 10-8 M. Our findings show that VA reduces the cell growth of prostate cancer cells and may interfere with the androgen receptor machinery. Of particular interest is the effect observed in PC-3 cells, in which VA seems to induce androgen sensitivity. It is worth noting that, in our experience, PC-3 cells show very low levels of androgen receptors (AR). Work is in progress to verify whether alterations in AR expression are involved in the modulation or induction of androgen sensitivity by VA