Cannabinoids' Role in Modulating Central and Peripheral Immunity in Neurodegenerative Diseases.

Cannabinoids (the endocannabinoids, the synthetic cannabinoids, and the phytocannabinoids) are well known for their various pharmacological properties, including neuroprotective and anti-inflammatory features, which are fundamentally important for the treatment of neurodegenerative diseases. The aging of the global population is causing an increase in these diseases that require the development of effective drugs to be even more urgent. Taking into account the unavailability of effective drugs for neurodegenerative diseases, it seems appropriate to consider the role of cannabinoids in the treatment of these diseases.

Selected cannabis cultivars modulate glial activation: in vitro and in vivo studies.

Introduction: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system characterized by neuroinflammation, demyelination and axonal loss. Cannabis, an immunomodulating agent, is known for its ability to treat MS effectively. However, due to variations in the profile of secondary metabolites, especially cannabinoids, among cannabis cultivars, the effectiveness of cannabis treatment can vary, with significant variability in the effects on different biological parameters.

An Emerging Strategy for Neuroinflammation Treatment: Combined Cannabidiol and Angiotensin Receptor Blockers Treatments Effectively Inhibit Glial Nitric Oxide Release.

Cannabidiol (CBD), the major non-psychoactive phytocannabinoid found in cannabis, has anti-neuroinflammatory properties. Despite the increasing use of CBD, little is known about its effect in combination with other substances. Combination therapy has been gaining attention recently, aiming to produce more efficient effects.

Therapeutic Potential of Phytocannabinoid Cannabigerol for Multiple Sclerosis: Modulation of Microglial Activation In Vitro and In Vivo.

Multiple sclerosis (MS) is a widespread chronic neuroinflammatory and neurodegenerative disease. Microglia play a crucial role in the pathogenesis of MS via the release of cytokines and reactive oxygen species, e.g.

Microglial Activation Is Modulated by Captopril: and Studies.

The renin-angiotensin system (RAS) is an important peripheral system involved in homeostasis modulation, with angiotensin II (Ang II) serving as the main effector hormone. The main enzyme involved in Ang II formation is angiotensin-converting enzyme (ACE). ACE inhibitors (ACEIs) such as captopril (Cap) are predominantly used for the management of hypertension.

Candesartan ameliorates brain inflammation associated with Alzheimer's disease.

Aims: Alzheimer's disease (AD) pathology is associated with brain inflammation involving microglia and astrocytes. The renin-angiotensin system contributes to brain inflammation associated with AD pathology. This study aimed to investigate the role of candesartan, an angiotensin II type 1 receptor blocker, in modulation of glial functions associated with AD.

Involvement of the Bradykinin B Receptor in Microglial Activation: and Studies.

The importance of brain inflammation to Alzheimer's disease (AD) pathogenesis has been accepted of late, with it currently being held that brain inflammation aggravates AD pathology. One important aspect of brain inflammation is the recruitment and activation of microglia, a process termed microgliosis. Kinins and bradykinin (BK), in particular, are major pro-inflammatory mediators in the periphery, although all of the factors comprising the kinin system have also been described in the brain.

Intranasal telmisartan ameliorates brain pathology in five familial Alzheimer's disease mice.

The renin-angiotensin system (RAS) is a major circulative system engaged in homeostasis modulation. Angiotensin II (Ang II) serves as its main effector hormone upon binding to its primary receptor, Ang II receptor type 1 (ATR). It is well established that an intrinsic independent brain RAS exists.

Angiotensin Converting Enzyme Inhibitors Ameliorate Brain Inflammation Associated with Microglial Activation: Possible Implications for Alzheimer's Disease.

Angiotensin converting enzyme (ACE) converts Angiotensin I to a potent vasoconstrictor angiotensin II (ANG II). ACE inhibitors (ACEIs) are widely used for the management of hypertension. All components of the renin-angiotensin system (RAS) have also been identified in the brain.

Telmisartan Modulates Glial Activation: In Vitro and In Vivo Studies.

The circulating renin-angiotensin system (RAS), including the biologically active angiotensin II, is a fundamental regulatory mechanism of blood pressure conserved through evolution. Angiotensin II components of the RAS have also been identified in the brain. In addition to pro-inflammatory cytokines, neuromodulators, such as angiotensin II can induce (through angiotensin type 1 receptor (AT1R)) some of the inflammatory actions of brain glial cells and influence brain inflammation.

Differential effect of intranasally administrated kinin B1 and B2 receptor antagonists in Alzheimer's disease mice.

An Increasing body of evidence supports a critical role of brain inflammation in the pathogenesis of Alzheimer's disease. A principal aspect of the brain immune response to inflammation is the activation of microglia. It has been shown that the kinin system is activated during brain inflammation and previously we demonstrated that bradykinin B1 receptor agonist reduced microglial activation in vitro.

Differential regulation of astrocyte prostaglandin response by kinins: possible role for mitogen activated protein kinases.

The role of kinins, well known as peripheral inflammatory mediators, in the modulation of brain inflammation is not completely understood. The present data show that bradykinin, a B2 receptor agonist, enhanced both basal and lipopolysaccharide (LPS)-induced cyclooxygenase-2 mRNA and protein levels and prostaglandin E2 synthesis in primary rat astrocytes. By contrast, Lys-des-Arg(9)-bradykinin, which is a bradykinin breakdown product and a selective kinin B1 receptor agonist, attenuated both basal and LPS-induced astrocyte cyclooxygenase-2 mRNA levels and prostaglandin E2 production.

Bradykinin decreases nitric oxide release from microglia via inhibition of cyclic adenosine monophosphate signaling.

Bradykinin (BK) is a major potent inflammatory mediator outside the central nervous system. In Alzheimer's disease, BK release and BK receptor expression in brain tissues are upregulated relatively early during the course of the disease. Hence, BK was believed to promote neuroinflammation.

Inhibitory role of kinins on microglial nitric oxide and tumor necrosis factor-α production.

Brain inflammation is sustained by chronic activation of microglia and the over-production of pro-inflammatory cytokines and nitric oxide (NO), which in turn can be highly neurotoxic. Microglial activation can be regulated by neuropeptides such as bradykinin (BK) and other members of the kinin family. Kinins are well known inflammatory regulators outside the CNS.

Distinct modulation of microglial amyloid β phagocytosis and migration by neuropeptides (i).

Microglial activation plays an integral role in the development and course of neurodegeneration. Although neuropeptides such as bradykinin (BK), somatostatin (SST), and endothelin (ET) are known to be important mediators of inflammation in the periphery, evidence of a similar function in brain is scarce. Using immunocytochemistry, we demonstrate the expression of receptors for BK (B1, B2 subtypes), ET (ETA, ETB subtypes) and SST (SST 2, 3, 4 subtypes) in primary microglia and microglial cell lines.

Glial response to lipopolysaccharide: possible role of endothelins.

Glial inflammation plays a major role in the development of neurodegenerative diseases. Although endothelins (ETs) are known as modulators of inflammation in the periphery, little is known about their possible role in brain inflammation. Previously, we demonstrated that all three endothelins (ET-1, ET-2 and ET-3) enhanced unstimulated synthesis of the glial pro-inflammatory mediators, prostaglandin E₂ (PGE₂) and nitric oxide (NO).

Protein synthesis dependent effects of kinins on astrocyte prostaglandin synthesis.

It has been shown that kinins and their receptors are over expressed in the brain under pathophysiological conditions such as inflammation. However, little is known about the possible role of kinins, and especially bradykinin in brain inflammation. Although kinins are thought to have immediate effects, peptides may also exert longer and protein synthesis dependent actions.

Inhibitory effect of carnosine and N-acetyl carnosine on LPS-induced microglial oxidative stress and inflammation.

Chronic inflammation and oxidative stress have been implicated in the pathogenesis of neurodegenerative diseases. A growing body of research focuses on the role of microglia, the primary immune cells in the brain, in modulating brain inflammation and oxidative stress. One of the most abundant antioxidants in the brain, particularly in glia, is the dipeptide carnosine, beta-alanyl-L-histidine.

Regulation of glial inflammatory mediators synthesis: possible role of endothelins.

Endothelins are well known as modulators of inflammation in the periphery, but little is known about their possible role in brain inflammation. Stimulation of astrocyte prostaglandin, an inflammatory mediator, synthesis was shown so far only by endothelin 3 (ET-3). By contrast, several studies showed no change or slight decrease of basal nitric oxide synthesis after treatment of astrocytes with endothelin 1 (ET-1) and ET-3.

Lipopolysaccharide differently affects prostaglandin E2 levels in fetal and maternal compartments of perfused human term placenta.

The aim of the present study was to examine the effect of lipopolysaccharide (LPS) on the levels of prostaglandin E(2) (PGE(2)) in the perfusates of the fetal and the maternal compartments of perfused human term placental tissue. Term placentas were perfused for 10h in the absence [control, (n=4)] and presence of LPS [LPS=1 microg/kg perfused placental tissue, (n=4)] in the maternal reservoir. Perfusate samples from the fetal and the maternal circulations were collected every 30 min and examined for PGE(2) levels by radio-immunoassay.

Inhibitory effect of somatostatin on prostaglandin E2 synthesis by primary neonatal rat glial cells.

Glial inflammation plays an integral role in the development of neurodegenerative disease. Although somatostatin is known to be a local anti-inflammatory factor in the periphery, evidence of a similar function in the brain is scarce. The aim of the present study was to investigate the effect of somatostatin on prostaglandin E(2) synthesis in primary neonatal rat glial cells.

Differential regulation of prostaglandin synthesis in neonatal rat microglia and astrocytes by somatostatin.

The aim of the present study was to investigate the role of somatostatin in the regulation of brain inflammation. We used lipopolysaccharide-induced prostaglandin E2 production in neonatal rat microglia and in astrocytes as a model of brain inflammation. Our data show an unexpected differential effect of somatostatin on lipopolysaccharide-induced prostaglandin E2 synthesis in rat microglia vs.

Regulation of glial cyclooxygenase by bradykinin.

The aim of the present study was to investigate the short-term effect of bradykinin on the two cyclooxygenase species in neonatal rat glial cells. In spite of the fact that cyclooxygenase protein levels were not altered, an increase in cyclooxygenase activity was observed. Use of cyclooxygenase-1 inhibitors and paracetamol resulted in complete elimination of the bradykinin-induced prostaglandin E(2) synthesis and of cyclooxygenase enzyme activity.

Kinins and neuroinflammation: dual effect on prostaglandin synthesis.

The role of kinins, well known as peripheral inflammatory mediators, in the modulation of brain inflammation is unclear. The present data show that bradykinin, a bradykinin B(2) receptor agonist, enhanced both basal and lipopolysaccharide-induced prostaglandin E(2) synthesis in rat neonatal glial cells in culture. By contrast, Lys-des-Arg(9)-bradykinin, which is a kinin breakdown product and a selective bradykinin B(1) receptor agonist, attenuated both basal and lipopolysaccharide-induced production of prostaglandin E(2) in glia.

Multiple effects of arginine vasopressin on prostaglandin E2 synthesis in fibroblasts.

Recent evidence supports the viewpoint that vasopressin, a neurohypophyseal peptide, should be also considered as a neuroendocrine modulator of immune and inflammatory responses. In this work we investigated the role of vasopressin in the regulation of prostaglandin E(2) synthesis by human dermal fibroblasts. Recombinant human interleukin-1 beta increased prostaglandin E(2) synthesis in fibroblasts about sixfold.