Therapeutic potential of α7 nicotinic receptor agonists to regulate neuroinflammation in neurodegenerative diseases

Neurodegenerative diseases, such as Alzheimer's, Parkinson's and Huntington's diseases, are all character-ized by a component of innate immunity called neuroinflammation. Neuronal loss and neuroinflammation are two phenomena closely linked. Hence, the neuroinflammation is a relevant target for the management of the neurodegenerative diseases given that, to date, there is no treatment to stop neuronal loss. Several studies have investigated the potential effects of activators of alpha 7 nicotinic acetylcholine receptors in animal models of neurodegenerative diseases. These receptors are widely distributed in the central nervous system. After activation, they seem to mediate the cholinergic anti-inflammatory pathway in the brain. This anti-inflammatory pathway, first described in periphery, regulates activation of microglial cells considered as the resident macrophage population of the central nervous system. In this article, we shortly review the agonists of the alpha 7 nicotinic acetylcholine receptors that have been evaluatedin vivo and we focused on the selective positive allosteric modulators of these receptors. These compounds represent a key element to enhance receptor activity only in the presence of the endogenous agonist.     

Diabetes mellitus and Parkinson's disease:dangerous liaisons between insulin and dopamine

The relationship between diabetes mellitus and Parkinson's disease has been described in several epidemiological studies over the 1960 s to date.Molecular studies have shown the possible functional link between insulin and dopamine,as there is strong evidence demonstrating the action of dopamine in pancreatic islets,as well as the insulin effects on feeding and cognition through central nervous system mechanism,largely independent of glucose utilization.Therapies used for the treatment of type 2 diabetes mellitus appear to be promising candidates for symptomatic and/or disease-modifying action in neurodegenerative diseases including Parkinson's disease,while an old dopamine agonist,bromocriptine,has been repositioned for the type 2 diabetes mellitus treatment.This review will aim at reappraising the different studies that have highlighted the dangerous liaisons between diabetes mellitus and Parkinson's disease.     

Tamoxifen:an FDA approved drug with neuroprotective effects for spinal cord injur y recover y

Spinal cord injury (SCI) is a condition without a cure, affecting sensory and/or motor functions. The physical trauma to the spinal cord initiates a cascade of molecular and cellular events that generates a non-permissive environment for cell survival and axonal regeneration. Among these complex set of events are damage of the blood-brain barrier, edema formation, inlfammation, oxidative stress, demyelination, reactive gliosis and apoptosis. The multiple events activated after SCI require a multi-active drug that could target most of these events and produce a permissive environment for cell survival, regeneration, vascular reorganization and syn-aptic formation. Tamoxifen, a selective estrogen receptor modulator, is an FDA approved drug with several neuroprotective properties that should be considered for the treatment of this devastating condition. Various investigators using different animal models and injury parameters have demonstrated the beneifcial effects of this drug to improve functional locomotor recovery after SCI. Results suggest that the mechanism of action of Tamoxifen administration is to modulate anti-oxidant, anti-inlfammatory and anti-gliotic responses. A gap of knowledge exists regarding the sex differences in response to Tamoxifen and the therapeutic window available to administer this treatment. In addition, the effects of Tamoxifen in axonal outgrowth or synapse formation needs to be investigated. This review will address some of the mechanisms activated by Tamoxifen after SCI and the results recently published by investigators in the ifeld.     

Overexpression of estrogen receptor beta alleviates the toxic effects of beta-amyloid protein on PC12 cells via non-hormonal ligands

After binding to the estrogen receptor, estrogen can alleviate the toxic effects of beta-amyloid protein, and thereby exert a therapeutic effect on Alzheimer’s disease patients. Estrogen can increase the incidence of breast carcinoma and endometrial cancer in post-menopausal women, so it is not suitable for clinical treatment of Alzheimer’s disease. There is recent evidence that the estrogen receptor can exert its neuroprotective effects without estrogen dependence. Real-time quantitative PCR and flow cytometry results showed that, compared with non-transfected PC12 cells, adenovirus-mediated estrogen receptor β gene-transfected PC12 cells exhibited lower expression of tumor necrosis factor α and interleukin 1β under stimulation with beta-amyloid protein and stronger protection from apoptosis. The Akt-specific inhibitor Abi-2 decreased the anti-inflammatory and anti-apoptotic effects of estrogen receptor β gene-transfection. These findings suggest that overexpression of estrogen receptor β can alleviate the toxic effect of beta-amyloid protein on PC12 cells, without estrogen dependence. The Akt pathway is one of the potential means for the anti-inflammatory and anti-apoptotic effects of the estrogen receptor.     

Neural functions of small heat shock proteins

Stress response is a cellular widespread mechanism encoded by a common protein program composed by multiple cellular factors that converge in a defense reaction to protect the cell against damage.Among many mechanisms described,heat shock proteins were proposed as universally conserved protective factors in the stress core proteome,coping with different stress stimuli through its canonical role in protein homeostasis.However,emerging evidences reveal non-canonical roles of heat shock proteins relevant for physiological and pathological conditions.Here,we review the implications of inducible heat shock proteins in the central nervous system physiology.In particular,we discuss the relevance of heat shock proteins in the maintenance of synapses,as a balanced protective mechanism in central nervous system development,pathological conditions and aging.     

Gengnianchun recipe inhibits apoptosis of pheochromocytoma cells from beta-amyloid 25-35 insult, better than monotherapies and their compounds

This study aims to determine and compare the protective effects of Gengnianchun recipe drug serum and compounds of its representative drug monotherapies against sympathetic nerve pheochromocytoma cell line PC12 cells damaged by beta-amyloid 25-35 at the cellular apoptosis and related signal pathway levels. PC12 cells cultured with medicated rat serum showed enhanced cell viability and reduced cellular apoptosis rates compared with those of monotherapies and their compounds. Furthermore, Gengnianchun recipe up-regulated expressions of anti-apoptotic protein Bcl-2, estrogen receptor-beta and phosphorylated extracellular-signal-regulated kinase 1/2; and down-regulated expressions of pro-apoptotic proteins Bax and caspase-3. Gengnianchun recipe was superior to representative drug monotherapies, such as paeoniflorin, berberine, timosaponin A-III, icariine and their compounds in protecting PC12 cells. Mitogen-activated protein kinase blocker and estrogen receptor antagonist were found to reverse the above effects of Gengnianchun recipe. The experimental findings indicate that, Gengnianchun recipe protects PC12 cells from beta-amyloid 25-35 insult; its inhibitory effect on apoptosis may be achieved through the mitogen-activated protein kinase and estrogen receptor pathways.     

Effects of fulvestrant on biological activity and Wnt expression in rat GH3 cells

The present study investigated the influence of anti-estrogen treatment (fulvestrant) on pituitary adenoma cell line GH3 biological activity, the estrogen receptor α pathway, the WnT pathway, and mechanisms of decreased Wnt inhibitory factor-1 expression in GH3 cells. Results showed that fulvestrant suppressed GH3 cell proliferation and reduced hormone secretion in a dose-dependent manner. Estrogen receptor α and Wnt4 expression decreased, but Wnt inhibitory factor-1 expression increased in a dose-dependent manner following fulvestrant treatment, and β-catenin expression remained unchanged. Inhibitors of DNA methylation and histone modification upregulated Wnt inhibitory factor-1 expression. Results suggested that fulvestrant suppressed biological activity of GH3 cells via the estrogen receptor α and Wnt pathways. These results suggested that decreased Wnt inhibitory factor-1 expression in GH3 cells played a role in epigenetic mechanisms. Anti-estrogen therapies could provide novel treatments for growth hormone adenomas.     

3,4-methylenedioxyamphetamine upregulates p75 neurotrophin receptor protein expression in the rat brain

The p75 neurotrophin receptor,which is a member of the tumor necrosis factor receptor superfamily,facilitates apoptosis during development and following central nervous system injury.Previous studies have shown that programmed cell death is likely involved in the neurotoxic effects of 3,4-methylenedioxy-N-methylamphetamine (MDMA),because MDMA induces apoptosis of immortalized neurons through regulation of proteins belonging to the Bcl-2 family.In the present study,intraperitoneal injection of different doses of MDMA (20,50,and 100 mg/kg) induced significant behavioral changes,such as increased excitability,increased activity,and irritability in rats.Moreover,changes exhibited dose-dependent adaptation.Following MDMA injection in rat brain tissue,the number of apoptotic cells dose-dependently increased and p75 neurotrophin receptor expression significantly increased in the prefrontal cortex,cerebellum,and hippocampus.These findings confirmed that MDMA induced neuronal apoptosis,and results suggested that this effect was related by upregulated protein expression of the p75 neurotrophin receptor.     

New perspectives for mesenchymal stromal cells as an adjuvant therapy for infectious disease-associated encephalopathies

Knowledge of the mechanisms that trigger infection-related encephalopathies is still very limited and cell therapies are one of the most promising alternatives for neurodegenerative diseases,and its application in infectious diseases can be of great relevance.Mesenchymal stromal cells are cells with great immunomodulatory potential;therefore,their use in clinical and preclinical studies in a variety of diseases,including central nervous system diseases,increased in the last decade.Mesenchymal stromal cells can exert their beneficial effects through several mechanisms,such as direct cell contact,through surface receptors,and also through paracrine or endocrine mechanisms.The paracrine mechanism is widely accepted by the scientific community and involves the release of soluble factors,which include cytokines,chemokines and trophic factors,and extracellular vesicles.This mini review discusses mesenchymal stromal cells mechanisms of action in neurological disorders,the neuroinflammatory process that takes place in the brain as a result of peripheral inflammation and changes in the brain’s cellular scenario as a common factor in central nervous system diseases,and mesenchymal stromal cells therapy in encephalopathies.Mesenchymal stromal cells have been shown to act in neuroinflammation processes,leading to improved survival and mitigating behavioral damage.More recently,these cells have been tested in preclinical models of infectious diseases-associated encephalopathies(e.g.,cerebral malaria and sepsis associated encephalopathy)and have shown satisfactory results.     

Steroids‐Dopamine Interactions in the Pathophysiology and Treatment of CNS Disorders

Introduction: Dopamine cell loss is well documented in Parkinson's disease and dopamine hypofunction is proposed in certain depressive states. At the opposite, dopamine hyperactivity is an enduring theory in schizophrenia with extensive supporting evidence. Aims: This article reviews the sex differences in these diseases that are the object of many studies and meta‐analyses and could be explained by genetic differences but also an effect of steroids in the brain. This article then focuses on the extensive literature reporting on the effect of estrogens in these diseases and effects of the other ovarian hormone progesterone as well as androgens that are less documented. Moreover, dehydroepiandrosterone, the precursor of estrogens and androgens, shows effects on brain dopamine neurotransmission that are reviewed. To investigate the mechanisms implicated in the human findings, animal studies are reviewed showing effects of estrogens, progesterone, and androgens on various markers of dopamine neurotransmission under intact as well as lesioned conditions. Discussion: For possible future avenues for hormonal treatments in these central nervous system diseases, we discuss the effects of selective estrogen receptor modulators (SERMs), the various estrogen receptors and their specific drugs as well as progesterone drugs. Conclusion: Clinical and experimental evidence supports a role of steroid–dopamine interactions in the pathophysiology of schizophrenia, depression and Parkinson's disease. Specific steroidal receptor agonists and SERMs are available for endocrine and cancer treatments and could find other applications as adjunct treatments in central nervous system diseases.     

Molecular mechanisms involved in the protective actions of Selective Estrogen Receptor Modulators in brain cells

Synthetic selective modulators of the estrogen receptors (SERMs) have shown to protect neurons and glial cells against toxic insults. Among the most relevant beneficial effects attributed to these compounds are the regulation of inflammation, attenuation of astrogliosis and microglial activation, prevention of excitotoxicity and as a consequence the reduction of neuronal cell death. Under pathological conditions, the mechanism of action of the SERMs involves the activation of estrogen receptors (ERs) and G protein-coupled receptor for estrogens (GRP30). These receptors trigger neuroprotective responses such as increasing the expression of antioxidants and the activation of kinase-mediated survival signaling pathways. Despite the advances in the knowledge of the pathways activated by the SERMs, their mechanism of action is still not entirely clear, and there are several controversies. In this review, we focused on the molecular pathways activated by SERMs in brain cells, mainly astrocytes, as a response to treatment with raloxifene and tamoxifen.     

Angiotensin-estrogen central interaction: Localization and mechanism

Intracerebroventricular (ICVT) administration of estradiol benzoate (EB) to ovariectomized female rats decreased drinking and pressor responses to central injections of angiotensinn II (AII). Estrogen treatment does not have this effect in male rats. As EB given ICVT reaches many brain areas, the site of action of EB was localized using crystalline implants of EB in the medial preoptic area or the ventromedial nucleus of the hypothalamus. These areas were chosen as they have a high density of estrogen receptors. Only medial preoptic area application of estrogen decreased angiotensin II-induced drinking. Angiotensin receptor binding was examined in homogenates from different brain regions to determine if the mechanism through which estrogen decreases central responses to AII involves altered receptor function. Systemic EB did not affect AII receptor binding in several brain regions but binding was decreased in homogenates from the preoptic area and septum-thalamus blocks which encompassed structures (median preoptic nucleus, organum vasculosum, and subfornical organ) implicated in central actions of AII. The sex specificity of the effect of estrogen was dependent on sexual differentiation of the brain. Manipulation of the neonatal hormone environment, which alters this brain differentiation, also altered the characteristic responses of the two sexes to estrogen. Neonatal androgenization of females, which causes masculinization and defeminization, resulted in animals which as adults no longer responded to EB with decreased drinking. On the other hand, preventing the development of a male brain by neonatal castration produced animals which as adults tended to decrease their drinking following estrogen. In summary, this study found that EB acts in the preoptic area to depress AII-induced responses by a site specific modulation of central AII receptors. Alteration of early brain development changed the responses of the two sexes to estrogen, perhaps by altering sexual differentiation of the preoptic area.     

Modulation of native and recombinant GABAA receptors by endogenous and synthetic neuroactive steroids

Upon administration, certain pregnane steroids produce clear behavioural effects including, anxiolysis, sedation, analgesia, anaesthesia and are anti-convulsant. This behavioural profile is characteristic of compounds that act to enhance the actions of GABA acting at the GABA_A receptor. In agreement, numerous studies have now demonstrated these steroids to be potent, positive allosteric modulators of the GABA_A receptor. The pregnane steroids are synthesized in the periphery by endocrine glands such as the adrenals and the ovaries, but are also made by neurons and glial cells in the central nervous system itself. Hence, these compounds could play both an endocrine and a paracrine role to influence neuronal excitability by promoting inhibition. Here we review evidence that the pregnane steroids are highly selective and extremely potent GABA_A receptor modulators and that their effects at ‘physiological’ concentrations (low nanomolar) may be influenced by the subunit composition of the GABA_A receptor. This feature may underlie recent findings demonstrating the effects of the neurosteroids on inhibitory synaptic transmission to be brain region dependent, although recent reports suggest that phosphorylation mechanisms may additionally influence neurosteroid sensitivity of the GABA_A receptor. Numerous synthetic steroids have been synthesized in an attempt to therapeutically exploit the behavioural effects of the pregnane steroids and progress with this approach will be discussed. However, the demonstration that the steroids may be made within the central nervous system offers the alternative strategy of targeting the enzymes that synthesize/metabolise the neurosteroids to exploit this novel endocrine/paracrine interaction.     

Neuroprotective effects of estrogens: potential mechanisms of action

Epidemiological studies associate post-menopausal estrogen use with a reduction in risk of Alzheimer's disease, a reduction in risk of Parkinson's disease, and death from stroke. The neuroprotective efficacy of estrogens have been well described and may contribute to these clinical effects. Estrogen-mediated neuroprotection has been described in several neuronal culture model systems with toxicities including serum-deprivation, beta-amyloid-induced toxicity, excitotoxicity, and oxidative stress. In animal models, estrogens have been shown to attenuate neuronal death in rodent models of cerebral ischemia, traumatic injury, and Parkinson's disease. Although estrogens are known to exert several direct effects on neurons, the cellular mechanisms behind the neuroprotective efficacy of the steroid are only beginning to be elucidated. In this review, we summarize the data supporting a neuroprotective role for estrogens in both culture and animal models and discuss neuronal effects of estrogens that may contribute to the neuroprotective effects. These effects include activation of the nuclear estrogen receptor, altered expression of bcl-2 and related proteins, activation of the mitogen activated kinase pathway, activation of cAMP signal transduction pathways, modulation of intracellular calcium homeostasis, and direct antioxidant activity.