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Lung cancer and cbd oil

findings 3.1. Preclinical

padalIIIik
18.02.2019

Content:

  • findings 3.1. Preclinical
  • Cannabinoids and Dementia: A Review of Clinical and Preclinical Data
  • A Role for Estrogen in Schizophrenia: Clinical and Preclinical Findings
  • ICH guideline S6 (R1) – preclinical safety evaluation of .. General principles. The objectives of the preclinical safety studies are to define pharmacological. PRECLINICAL FINDINGS ON SP AND NK1R Preclinical Findings in Affective Disorders Beginning in the mids, several groups began examining a. symptoms of dementia. 3. Results and Discussion. Preclinical findings. Alzheimer's disease. Alzheimer's disease is characterized by.

    findings 3.1. Preclinical

    Furthermore, it should be evaluated whether the administration of CBD in combination with CB 1 agonists or alone could slow the neurodegenerative process in patients suffering from HD and PD. Cannabinoid based drugs may therefore become a therapeutic option to modify the course of neurodegenerative diseases. The small but successful human trials with CB 1 agonists in HD and AD that ameliorated behavioral disturbances are promising.

    The reported beneficial effects of Nabilone in HD or dronabinol in AD with behavioral disturbances call for replication in larger trials covering longer periods of observation. Given, that both substances prove to be save in long term administration, Dronabinol and Nabilone could soon become an adjunct treatment option in these severe conditions, i.

    The transition of findings from bench to bedside and the extension of results from small clinical trials should be on the research agenda for the near future. Because treatment strategies for dementia are so preliminary at the current state of knowledge and the need for a cure is so desperate, it is worth pursuing the quest for one or more cannabinoid compounds in the field.

    National Center for Biotechnology Information , U. Journal List Pharmaceuticals Basel v. Published online Aug Author information Article notes Copyright and License information Disclaimer. This article is an Open Access article distributed under the terms and conditions of the Creative Commons Attribution license http: This article has been cited by other articles in PMC.

    Abstract The endocannabinoid system has been shown to be associated with neurodegenerative diseases and dementia. Table 1 Cannabinoids mentioned in this paper. Open in a separate window. Results and Discussion 3. Effects mediated via cb 1 and cb 2 Receptors In AD brains cannabinoid receptor binding was reduced in the hippocampal formation and caudate [ 39 ], whereas the mRNA levels did not differ from controls. Vascular dementia Vascular dementia develops as a consequence of brain ischemia.

    Vascular dementia Currently, there are no studies or case reports on cannabinoids in patients with vascular dementia. Conclusions Several lines of evidence have demonstrated the role of cannabinoids in dementia. Global prevalence of dementia: A delphi consensus study.

    Risk of dementia in parkinson's disease: A community-based, prospective study. Pathogenesis to animal models. Strategies for disease modification. The endocannabinoid system as an emerging target of pharmacotherapy. Isolation, structure, and partial synthesis of active constituent of hashish. Structure of a cannabinoid receptor and functional expression of the cloned cdna.

    Molecular characterization of a peripheral receptor for cannabinoids. The functional neuroanatomy of brain cannabinoid receptors.

    Alzheimer's disease; taking the edge off with cannabinoids? International union of pharmacology. Classification of cannabinoid receptors. Cannabinoid physiology and pharmacology: The diverse cb1 and cb2 receptor pharmacology of three plant cannabinoids: Delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Neurobiology and systems physiology of the endocannabinoid system. Endocannabinoid signaling in the brain. Formation and inactivation of endogenous cannabinoid anandamide in central neurons.

    Cannabinoid receptors in the human brain: A detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Cannabinoid receptor localization in brain. Distribution of cb1 cannabinoid receptors in the amygdala and their role in the control of gabaergic transmission.

    Presynaptically located cb1 cannabinoid receptors regulate gaba release from axon terminals of specific hippocampal interneurons. Emerging role from neurodevelopment to neurodegeneration.

    The endocannabinoid system and alzheimer's disease. Cannabinoid system in neurodegeneration: New perspectives in alzheimer's disease. The endocannabinoid system as a target for the treatment of motor dysfunction. Role of cannabinoids and endocannabinoids in cerebral ischemia.

    The endocannabinoid system and huntington's disease. Deciphering the molecular basis of memory failure in alzheimer's disease. A promising drug for neurodegenerative disorders? Cannabinoid receptor stimulation is anti-inflammatory and improves memory in old rats. Anti-inflammatory property of the cannabinoid agonist win in a rodent model of chronic brain inflammation.

    Molecular composition of the endocannabinoid system at glutamatergic synapses. Inflammatory neurodegeneration mediated by nitric oxide from activated glia-inhibiting neuronal respiration, causing glutamate release and excitotoxicity.

    Nonpsychotropic cannabinoid receptors regulate microglial cell migration. Cannabinoid receptor binding and messenger rna expression in human brain: An in vitro receptor autoradiography and in situ hybridization histochemistry study of normal aged and alzheimer's brains. Cannabinoid cb2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in alzheimer's disease brains.

    Prevention of alzheimer's disease pathology by cannabinoids: Neuroprotection mediated by blockade of microglial activation. Cannabinoid receptor agonists inhibit glutamatergic synaptic transmission in rat hippocampal cultures. Cannabinoid receptor agonists protect cultured rat hippocampal neurons from excitotoxicity.

    Cb1 cannabinoid receptors and on-demand defense against excitotoxicity. Anandamide, but not 2-arachidonoylglycerol, accumulates during in vivo neurodegeneration. Neuroprotection by delta9-tetrahydrocannabinol, the main active compound in marijuana, against ouabain-induced in vivo excitotoxicity. Exogenous anandamide protects rat brain against acute neuronal injury in vivo. Anandamide and noladin ether prevent neurotoxicity of the human amyloid-beta peptide.

    Cb1 receptor selective activation inhibits beta-amyloid-induced inos protein expression in c6 cells and subsequently blunts tau protein hyperphosphorylation in co-cultured neurons.

    Involvement of brain-derived neurotrophic factor in cannabinoid receptor-dependent protection against excitotoxicity. Endogenous interleukin-1 receptor antagonist mediates anti-inflammatory and neuroprotective actions of cannabinoids in neurons and glia. Comparison analysis of gene expression patterns between sporadic alzheimer's and parkinson's disease.

    Stimulation of cannabinoid receptor 2 cb2 suppresses microglial activation. Modulation of the cannabinoid cb2 receptor in microglial cells in response to inflammatory stimuli. The activation of cannabinoid cb2 receptors stimulates in situ and in vitro beta-amyloid removal by human macrophages.

    A molecular link between the active component of marijuana and alzheimer's disease pathology. Neuroprotective effect of cannabidiol, a non-psychoactive component from cannabis sativa, on beta-amyloid-induced toxicity in pc12 cells. Cannabidiol inhibits inducible nitric oxide synthase protein expression and nitric oxide production in beta-amyloid stimulated pc12 neurons through p38 map kinase and nf-kappab involvement.

    Cannabidiol in vivo blunts beta-amyloid induced neuroinflammation by suppressing il-1beta and inos expression. Cannabidiol prevents infarction via the non-cb1 cannabinoid receptor mechanism. Drug-induced hypothermia reduces ischemic damage: Effects of the cannabinoid hu The effect of deltatetrahydrocannabinol on forebrain ischemia in rat. Neuroprotective and brain edema-reducing efficacy of the novel cannabinoid receptor agonist bay Cannabinoids and neuroprotection in global and focal cerebral ischemia and in neuronal cultures.

    Increased severity of stroke in cb1 cannabinoid receptor knock-out mice. Delta9-tetrahydrocannabinol thc and am protect against cerebral ischaemia in gerbils through a mechanism involving cannabinoid and opioid receptors. The endocannabinoid system in the mechanisms of neuronal death. The "Dark side" Of endocannabinoids: A neurotoxic role for anandamide. Epidemiological studies of the effect of stroke on incident dementia: Loss of cannabinoid receptors in the substantia nigra in huntington's disease.

    The pattern of neurodegeneration in huntington's disease: A comparative study of cannabinoid, dopamine, adenosine and gaba a receptor alterations in the human basal ganglia in huntington's disease. Selective vulnerability in huntington's disease: Preferential loss of cannabinoid receptors in lateral globus pallidus. Cannabinoid cb 1 , gaba a and gaba b receptor subunit changes in the globus pallidus in huntington's disease. Cannabinoid receptor messenger rna levels decrease in a subset of neurons of the lateral striatum, cortex and hippocampus of transgenic huntington's disease mice.

    Structure, expression and regulation of the cannabinoid receptor gene cb1 in huntington's disease transgenic mice. Loss of mrna levels, binding and activation of gtp-binding proteins for cannabinoid cb1 receptors in the basal ganglia of a transgenic model of huntington's disease. Delayed onset of huntington's disease in mice in an enriched environment correlates with delayed loss of cannabinoid cb1 receptors.

    Changes in endocannabinoid transmission in the basal ganglia in a rat model of huntington's disease. A cell-based screen for drugs to treat huntington's disease. Effects of cannabinoids in the rat model of huntington's disease generated by an intrastriatal injection of malonate. Cortical expression of brain derived neurotrophic factor and type-1 cannabinoid receptor after striatal excitotoxic lesions.

    Microglial cb2 cannabinoid receptors are neuroprotective in huntington's disease excitotoxicity. Early and progressive accumulation of reactive microglia in the huntington disease brain. Progressive striatal and cortical dopamine receptor dysfunction in huntington's disease: Microglial activation in presymptomatic huntington's disease gene carriers. Arvanil, a hybrid endocannabinoid and vanilloid compound, behaves as an antihyperkinetic agent in a rat model of huntington's disease. Alleviation of motor hyperactivity and neurochemical deficits by endocannabinoid uptake inhibition in a rat model of huntington's disease.

    A novel population of progenitor cells expressing cannabinoid receptors in the subependymal layer of the adult normal and huntington's disease human brain. The cannabinoid cp55, prolongs survival and improves locomotor activity in drosophila melanogaster against paraquat: Implications in parkinson's disease.

    Cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity in vivo and in vitro: Relevance to parkinson's disease. Evaluation of the neuroprotective effect of cannabinoids in a rat model of parkinson's disease: Importance of antioxidant and cannabinoid receptor-independent properties.

    Win55,, a cannabinoid receptor agonist, protects against nigrostriatal cell loss in the 1-methylphenyl-1,2,3,6-tetrahydropyridine mouse model of parkinson's disease. The cannabinoid receptor agonist win 55, reduces d2, but not d1, dopamine receptor-mediated alleviation of akinesia in the reserpine-treated rat model of parkinson's disease.

    Enhanced levels of endogenous cannabinoids in the globus pallidus are associated with a reduction in movement in an animal model of parkinson's disease. Striatal cannabinoid cb1 receptor mrna expression is decreased in the reserpine-treated rat model of parkinson's disease.

    Experimental parkinsonism alters endocannabinoid degradation: Implications for striatal glutamatergic transmission. Cb1 cannabinoid receptor inhibits synaptic release of glutamate in rat dorsolateral striatum.

    The cb 1 antagonist rimonabant is adjunctively therapeutic as well as monotherapeutic in an animal model of parkinson's disease. Blockade of cannabinoid type 1 receptors augments the antiparkinsonian action of levodopa without affecting dyskinesias in 1-methylphenyl-1,2,3,6-tetrahydropyridine-treated rhesus monkeys.

    Cannabinoid cb1 antagonists possess antiparkinsonian efficacy only in rats with very severe nigral lesion in experimental parkinsonism. Cannabinoid receptor agonist and antagonist effects on motor function in normal and 1-methylphenyl-1,2,5,6-tetrahydropyridine mptp -treated non-human primates.

    Therapeutic effects of delta9-thc and modafinil in a marmoset parkinson model. Stimulation of cannabinoid receptors reduces levodopa-induced dyskinesia in the mptp-lesioned nonhuman primate model of parkinson's disease. The cb1 cannabinoid receptor agonist, hu, reduces levodopa-induced rotations in 6-hydroxydopamine-lesioned rats. Neurochemical changes in the striatum of dyskinetic rats after administration of the cannabinoid agonist win55, A review of recent evidence for prevention and treatment.

    Cannabinoids for the treatment of dementia. Effects of dronabinol on anorexia and disturbed behavior in patients with alzheimer's disease. Deltatetrahydrocannabinol for nighttime agitation in severe dementia. Comprehensive assessment of psychopathology in dementia.

    The cannabinoid receptor agonist nabilone for the treatment of dementia-related agitation. Lack of cb1 receptor activity impairs serotonergic negative feedback. Cannabinoids elicit antidepressant-like behavior and activate serotonergic neurons through the medial prefrontal cortex. Bimodal control of stimulated food intake by the endocannabinoid system. The role of the cb1 receptor in the regulation of sleep. Anandamide enhances extracellular levels of adenosine and induces sleep: An in vivo microdialysis study.

    Behavioural and psychological symptoms in vascular dementia; differences between small and large vessel disease. Enhancement of endocannabinoid signaling and the pharmacotherapy of depression. A pilot study using nabilone for symptomatic treatment in huntington's disease.

    Controlled clinical trial of cannabidiol in huntington's disease. Nabilone could treat chorea and irritability in huntington's disease. Nabilone increases choreatic movements in huntington's disease. Survey on cannabis use in parkinson's disease: Subjective improvement of motor symptoms. Open label evaluation of cannabidiol in dystonic movement disorders.

    Cannabinoids reduce levodopa-induced dyskinesia in parkinson's disease: Cannabis for dyskinesia in parkinson disease: A randomized double-blind crossover study. Neurokinin b, neurotensin, and cannabinoid receptor antagonists and parkinson disease. Cannabidiol for the treatment of psychosis in parkinson's disease. Support Center Support Center.

    Please review our privacy policy. CB 1 and CB 2 agonist. Women with schizophrenia are often hypoestrogenic; that is, their circulating levels of estrogen are much lower than the normal reference range and they tend to experience menstrual irregularities [ 48 , 49 , 55 ].

    Importantly, some studies showing reduced estrogen levels in women with schizophrenia were conducted during the preantipsychotic era [ 56 , 57 ]. Since the introduction of antipsychotic drug treatment, reduction in estrogen levels is correlated with an increased risk of symptoms and is found regardless of the type of antipsychotic treatment [ 47 , 58 ].

    This is important as some antipsychotics can cause hyperprolactinaemia, which leads to a reduction in estrogen levels [ 59 ]. Hyperprolactinaemia is mainly associated with antipsychotics, such as risperidone, which predominantly block the dopamine D2 receptor, the receptor that modulates prolactin release from the pituitary [ 60 ]. An important question is whether estrogen dysfunction occurs prior to or after the onset of schizophrenia. Early puberty has been associated with a late onset of the disorder [ 38 ], suggesting that physiological estrogens might delay the onset of schizophrenia [ 56 ].

    Many clinical studies examining plasma estrogen levels and symptomatology in schizophrenia patients require their participants to have a history of regular menstrual cycles; therefore it cannot be inferred from these samples whether gonadal dysfunction is merely a state or a trait of the disorder.

    Schepp [ 61 ] attempted to explore this question by investigating premenopausal first-episode schizophrenia patients. In comparison to age-matched healthy controls, schizophrenia patients had later menarche, mid-cycle bleeding, mild bleeding, hirsutism, and more tendency to be infertile [ 56 , 61 ]. This study demonstrates evident gonadal dysfunction in a sample of first-time admitted patients; however, a longitudinal experiment examining endocrinological function, inclusive of prepubescent participants, is necessary to sufficiently answer whether premorbid hypoestrogenism occurs.

    A growing body of double-blind, placebo-controlled, randomized trials provides evidence that estrogen treatment administered in conjunction with antipsychotics is beneficial for schizophrenia, particularly in reducing the positive symptoms [ 20 , 62 , 63 ]. An initial pilot study by Kulkarni et al. Later trialling a transdermal method of administration, Kulkarni et al. Another group found similar beneficial effects, where 8 weeks of adjunctive haloperidol and ethinylestradiol treatment resulted in reduced positive, general, and total PANSS scores, compared to the haloperidol-only group [ 62 ].

    On the other hand, a study by Bergemann and colleagues [ 65 ] failed to replicate the beneficial effect of estradiol in their placebo-controlled, double-blind study with 46 hypoestrogenic women, finding there was no difference in PANSS scores, relapse rates, or antipsychotic dose between treatment and placebo.

    In comparison, Kulkarni et al. One cross-sectional study compared postmenopausal women with schizophrenia who were either users or nonusers of hormone replacement therapy. They found that the women taking hormones required a lower dose of antipsychotics and had less severe negative symptoms [ 66 ].

    Research thus far has primarily concerned females, evidently due to the premise for estrogen therapy relying on observation of hypoestrogenism in women. One study that examined the effects of estradiol in men with schizophrenia found that after two weeks of oral estradiol treatment in conjunction with antipsychotics, the estrogen group experienced more rapid reduction in general psychopathology compared to the placebo group [ 67 ].

    Although there is concern regarding the potentially feminising side effects of estradiol, estrogen therapy is currently used in males for other clinical conditions e. In a double-blind, randomized, placebo-controlled trial, 32 premenopausal women with chronic schizophrenia were treated with conjugated estrogens for 4 weeks, in addition to their antipsychotic treatment.

    Participants experienced a significant decrease in positive, negative, general, and total PANSS scores [ 68 ]. The selective estrogen receptor modulator raloxifene has also been trialled in women with schizophrenia with favourable results for the positive [ 70 , 71 ], negative [ 72 ], and cognitive symptoms [ 73 , 74 ].

    Clinical research specifically concerning the influence of estradiol on cognition in schizophrenia patients is limited. With relevance to endogenous estrogen, research has found estradiol can improve certain cognitive functions in women with schizophrenia. Ko and colleagues [ 76 ] stratified their sample of women with schizophrenia into low or high estrogen groups by using the normal serum reference ranges for estradiol during the follicular phase of the menstrual cycle.

    Similar to the results of Hoff et al. Studies administering estradiol treatment provide less consistent results. These studies employed different neurocognitive batteries and different methods of administering estradiol, which may account for dissimilar outcomes. The diverse results in the aforementioned estradiol trials may be due to a variety of inconsistent factors including dissimilar measures, severity of symptoms, variable treatment duration, additional pharmacotherapy i.

    Additionally, despite its putative effect on the positive symptoms of schizophrenia, estradiol at the efficacious dose is unfortunately not feasible for long-term management of schizophrenia due to the associated health risks e. Evidently, estradiol treatment in men with schizophrenia also remains controversial due to potential feminising side effects [ 20 , 67 ].

    Nevertheless, overall the epidemiological and clinical data presented provide strong support for the notion that estradiol is protective in women with schizophrenia, particularly for the positive symptoms. The molecular mechanisms of how estrogen may affect schizophrenia symptoms remain largely unknown. Perhaps the simplest explanation is that estrogen can regulate the dopaminergic system of the central nervous system CNS by affecting the expression and function of dopamine receptors and transporters [ 78 , 79 ].

    However, there are several other possible mechanisms by which estradiol can exert the effects in the CNS, some of which have been well defined and others are yet to be characterised.

    Estradiol actions are generally categorised as either genomic or nongenomic. Genomic actions are delayed in onset and prolonged in duration, such as those likely to occur after chronic estradiol treatment. These effects occur through binding of intracellular estradiol to the estrogen receptor ER , which belongs to the nuclear receptor superfamily. The nongenomic actions occur through activation of intracellular second messenger pathways, such as the MAP kinase and cAMP, to elicit a more rapid response, including cell-excitability, synaptic transmission, and antioxidant effects [ 80 — 82 ].

    These are believed to be mediated via either ERs interacting with other proteins to form a large complex anchored to the plasma membrane or an alternative G protein coupled receptor, GPR30 [ 83 , 84 ] see Figure 1. Gene profiling of the mouse brain after treatment with estradiol has revealed changes in genes associated with biosynthesis, growth, synaptic potentiation and myelination, lipid synthesis and metabolism, cell signalling pathways, and epigenetic modifications [ 85 , 86 ].

    In the primate prefrontal cortex, estrogen treatment caused changes in genes involved in transcription regulation, neurotransmission, cell signalling, cell cycle control, and proliferation and differentiation [ 87 ]. These effects could be a result of either genomic or nongenomic actions [ 88 ]. Thus estrogen can have far-reaching and diverse effects on the brain. Interestingly, one group studied the gene expression profile of a cell line treated with 18 different antipsychotics and found a common signature shared by antipsychotics and estrogen receptor modulators: It is theorised that the estrogen pathway may be involved in the therapeutic effect of antipsychotics [ 89 ].

    For many years there was uncertainty surrounding the role of ERs in nongenomic actions of estrogen. GPR30, previously an orphan receptor, was recently renamed G protein coupled estrogen receptor 1 GPER following evidence that estrogen can bind to and activate the receptor [ , ].

    It is found to be expressed in multiple regions of the rat CNS [ ], including the hippocampus, frontal cortex, and substantia nigra [ 94 , ]. Several studies indicate that this receptor is localised to the cytoplasm [ ], specifically the endoplasmic reticulum and Golgi apparatus [ 90 , , ].

    However there is also evidence that it is expressed at the plasma membrane and dendritic spines of rat hippocampal neurons [ , — ], suggesting that localisation may be cell type-specific or influenced by state.

    This receptor can rapidly activate multiple kinase pathways involved in nongenomic estrogen actions [ ] and appears to mediate many of the effects of estrogen in neuronal cells [ ], including calcium oscillations and luteinising hormone-releasing activity in primate neurons [ ]. While CNS expression patterns do not appear to differ between the adult male and female rat [ , , ], the receptor is implicated in sexual dimorphism of immune response in the GPER knock-out mouse [ ].

    Importantly, there is emerging evidence for GPERs role in learning and memory [ — ] as well as neuronal plasticity [ ]. Several new members and isoforms of estrogen receptors have also recently been identified, some of which are expressed in the CNS, such as ER-X, which could be involved in the nongenomic actions of estrogen [ ]; however these have yet to be well characterised [ ].

    The role of estrogen on cognition is of particular importance for schizophrenia as the cognitive deficits associated with the disease are considered the most debilitating symptoms for patients to assimilate into society [ ], and these symptoms are poorly treated using current antipsychotics [ ].

    Sinopoli and colleagues [ ] showed that a low dose of estradiol injected directly into the hippocampus, or a high dose injected into the prefrontal cortex, could improve radial arm maze performance spatial working memory task in rats [ ]. Molecular work by the same authors showed that memory enhancements via DPN are likely to occur through alterations in monoamines in the hippocampus and prefrontal cortex [ ]. In a different species, Phan et al. Collectively, research demonstrates that different estrogen agonists, estrogen receptors, and brain regions have the ability to mediate dissimilar forms of learning and memory.

    It is currently difficult to isolate specific actions of ERs in relation to cognitive function. Not only does function change dependent on the cognitive task, but factors such as age, sex, and treatment duration can also alter outcomes. The latter is of particular importance due to the influence of treatment period on genomic versus nongenomic outcomes and consequently mediation via different estrogen receptors [ ]. More preclinical research is necessary to further clarify the specific role of ERs in relation to cognition, especially with specific relevance to schizophrenia.

    Schizophrenia is associated with various structural brain changes, such as progressive decline in global gray and white matter volume in multiple brain regions followed by continuous ventricular enlargement [ ].

    Abnormal cytoarchitecture also commonly occurs, including neuronal soma and neuropil volume reductions, irregular synaptic organization, and ectopic neurons [ , ]. The effects of estrogen treatment on brain structure have been well documented, including the modulation of neurogenesis, synaptic density, plasticity and connectivity, and axonal sprouting reviewed in [ 84 ].

    Of particular relevance to cognition, estradiol treatment has been shown to enhance hippocampal synaptic plasticity in young ovariectomised rats [ ], induce dendritic spine formation in CA1 pyramidal neurons [ ], and stimulate neurogenesis of granule cells in the dentate gyrus of adult female rats [ ].

    Estrogen can also modulate neurotrophic factors [ ] as well as neurotransmission [ 15 , ], which can secondarily promote neuronal survival and proliferation. Thus, in women with schizophrenia, lower circulating estradiol levels [ 51 , 65 ] may contribute to the observed brain pathology associated with the disorder. Based on these findings we would expect to see sex differences in brain abnormalities in people with schizophrenia.

    Indeed, two MRI studies reported more severe abnormalities in males than in females with the disorder when compared to age- and sex-matched controls, particularly in regard to ventricular enlargement [ 37 ] and temporal lobe volume [ 35 ]. However there are some conflicting reports, where a similar MRI study showed no difference [ ].

    Overall these studies suggest that estrogen levels could influence the brain structure differences that occur in the CNS of people with schizophrenia. Neuroprotective effects are another key component of estrogen action that is relevant to schizophrenia [ 84 ]. Early cell culture studies showed increased neuronal survival upon treatment with estrogen under serum deprivation [ — ] and subsequent studies have shown estrogen protection against injury from excitotoxicity [ — ], oxidative stress [ , ], inflammation [ , ], and apoptosis [ ].

    Some of these protective actions have been attributed to the ability of estrogen to reduce the generation of free radicals [ ]. More recently, it has been suggested that the neuroprotective actions of estrogen are mediated through maintaining mitochondria function [ ], and there is growing evidence of mitochondrial dysfunction playing a role in schizophrenia [ ]. Taken together, these findings indicate that low estrogen levels may leave the brain vulnerable to insult or age-related changes, leading to development of schizophrenia or increased symptom severity, and could explain the observed differences in disease onset and severity between males and females.

    Treatment with estrogen may therefore help to protect the brain from disease progression. This has implications in estrogen driven synaptic plasticity and neurogenesis, as this region of the hippocampus is important for control of these activities.

    Further, lower receptor levels are unlikely to be the result of lower circulating estradiol levels as low levels of hormone would be expected to upregulate receptor expression [ ].

    More recently, ER gene variation has also been implicated in schizophrenia risk. Several converging lines of evidence from clinical and animal studies suggest that estrogen can act to modulate the activity of the neurotransmitter systems targeted by current antipsychotics [ 30 , 79 , 83 , ]. Understanding the nature of these interactions is important for addressing the therapeutic potential of estrogen and of compounds that target estrogen signalling.

    Researchers have labelled estradiol as neuroprotective and antipsychotic, implicating numerous neurotransmitter systems in this mechanism [ 30 ]. The strongest evidence for estrogen modulation of neurotransmitter systems comes from studies examining the dopamine, serotonin, and glutamate systems; examples of these studies are described below.

    As stated earlier the most direct route by which estrogen could influence symptom severity in schizophrenia could be by modulating dopaminergic activity in the CNS as hyperactivation of the dopamine signalling system is thought to be a central mechanism affected in schizophrenia [ 12 , ].

    Central to this hypothesis are observations that typical antipsychotics, such as haloperidol, are potent antagonists of dopamine D2 receptors [ ] and can reduce positive symptoms of schizophrenia [ ]. The stimulatory effect of estrogen on the activity of dopaminergic neurons, particularly those in the striatum and nucleus accumbens, is well documented see [ 79 ]. Rodent studies have demonstrated that phases of dopaminergic transmission vary during the estrous cycle [ ]. Removal of the primary source of estradiol via ovariectomy evokes a permanent loss of dopamine neuron density in the substantia nigra in nonhuman primates [ ].

    Estradiol treatment can modulate the levels of dopamine transporters and receptors pre- and postsynaptic and dopamine synthesis, release, and turnover in both cortical and striatal regions [ , — ]. For example, ovariectomy in rats has been shown to reduce protein levels of the dopamine active transporter which reuptakes dopamine into the neuron for recycling or degradation and increase levels of dopamine D2 receptor in the nucleus accumbens and caudate nucleus [ 78 ].

    In humans, a PET study did not show any significant variation in striatal D2 receptor density throughout the menstrual cycle [ ]. However, postmenopausal women receiving estrogen replacement therapy following hysterectomy or oophorectomy showed increased dopamine responsiveness to apomorphine [ ]. Rodent behaviour studies also show marked protective effects of estrogen on the dopaminergic system.

    For example, we measured a behavioural endophenotype of schizophrenia, prepulse inhibition, in ovariectomised female rats treated with estrogen and its analogues [ ]. Interestingly, this effect of estradiol was not observed when paired with saline treatment, suggesting that estradiol exerts antipsychotic properties that further potentiate the functional efficacy of haloperidol.

    However, the lack of a haloperidol treatment-only group in this study makes it difficult to ascertain this facilitatory effect. Overall, these studies suggest a protective action of estrogen, particularly in females, on the dopaminergic system.

    The advent of clinically effective atypical antipsychotics which have a higher affinity for serotonin receptors compared to typical antipsychotics, has highlighted a role for the serotonergic system in schizophrenia [ , , ]. Further, postmortem studies have reported altered levels of several serotonin receptors in cortical and subcortical regions of the CNS in people with schizophrenia [ — ].

    Cannabinoids and Dementia: A Review of Clinical and Preclinical Data

    Shared data mainly from short term preclinical studies in rat via oral .. Analysis by species. Analysis of how the eTOX non-confidential shared. What Types of Studies Are Within Scope for SEND ? 11 The Next SEND Release: Version rapidly across species, compounds, and clinical and preclinical disciplines in ways that are not currently feasible. These standards and. Preclinical findings. Alzheimer's disease. Alzheimer's disease is characterized by extracellular neuritic.

    A Role for Estrogen in Schizophrenia: Clinical and Preclinical Findings



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    Shared data mainly from short term preclinical studies in rat via oral .. Analysis by species. Analysis of how the eTOX non-confidential shared.

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