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BACKGROUND: The effects of collagen-induced arthritis (CIA), a model of systemic inflammation, on brain regional molecular markers associated with neurological disorders are uncertain. OBJECTIVE: This study investigated the brain regional molecular changes in markers associated with inflammation and neuronal dysfunction in a CIA model. METHODS: Fourteen male Sprague Dawley rats were divided into control (n = 5) or CIA (n = 9) groups. 10 weeks after CIA induction, brain tissue was collected. Brain regional mRNA expression of inflammatory markers (IL-1ß and IL-6), apoptotic markers (BAX and Bcl2) and neurotrophic factors (BDNF, CREB and TrkB) was determined. Monoamine distribution and abundance in different brain regions were determine by mass spectrometry imaging (MSI). RESULTS: Neuroinflammation was confirmed in the CIA group by increased IL-ß mRNA expression, concurrent with an increased BAX/Bcl2 ratio. The mRNA expression of CREB was increased in the midbrain and hippocampus while BDNF was increased and TrkB was decreased across all brain regions in CIA compared to control animals. Serotonin was decreased in the midbrain and hippocampus while dopamine was decreased in the striatum of CIA rats, compared to controls. CONCLUSION: CIA resulted in neuroinflammation concurrent with an apoptotic state and aberrant expression of neurotrophic factors and monoamines in the brain, suggestive of neurodegeneration.
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Renal dysfunction is important in preeclampsia (PE) pathophysiology and has not been fully explored in the arginine vasopressin (AVP) rat model of PE. This study aimed to determine kidney toxicity associated with this model. Female Sprague Dawley rats (n = 24) were subcutaneously infused with AVP or saline for 18 days. Urine samples (GD8, 14 and 18) were used to determine the levels of albumin, VEGF-A, clusterin, NGAL/Lipocalin-2, KIM-1, cystatin C, TIMP-1, ß2M and OPN via Multiplex ELISAs. Albumin, and NGAL/lipocalin-2 were significantly elevated in the PAVP vs PS group on GD14 and GD18 (p < 0.001) respectively. VEGF-A significantly decreased in the pregnant vs non-pregnant groups on GD14 and 18 (p < 0.001). Clusterin (p < 0.001) and OPN (p < 0.05) were significantly higher in the PAVP vs PS group on GD18. Cystatin C and KIM-1 are significantly upregulated in the PAVP vs PS groups throughout gestation (p < 0.05). ß2M is significantly elevated in the PAVP vs PS group on GD14 and 18 (p < 0.05). AVP elevated the urinary levels of the kidney injury biomarkers and replicated the renal dysfunction associated with PE development. Our findings confirm the potential applications of this model in studying the mechanisms underlying renal damage in PE.
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In Africa, there is currently a paucity of data on the epidemiology of depression, its treatment and management. The prevalence of depression is severely underestimated, with unique circumstances and societal risk factors associated with depression and its public awareness. Treating and managing depression is confounded by an inaccessibility to efficient and low-cost treatments for patients with depression. The aetiology of depression is multifactorial, with various theories implicating multiple neuronal networks. Despite this, the treatment of depression is one-dimensional focussing on outdated theories of depression and mainly targeting dysfunctional neurotransmitter pathways. Hence, it is not surprising that there is a significant increase in the prevalence of patients suffering from treatment resistant depression (TRD), with a large portion of patients deriving little clinical benefit from these traditional anti-depressant therapies. This highlights the need for more effective treatment strategies for depression, especially applicable to resource limited environments such as Africa, where there is little investment in public healthcare resources towards managing mental health disorders. The clinical potential of using ketamine in managing depression has received considerable attention in the past two decades, with the FDA approving esketamine for the management of TRD in 2019. This widespread attention has significantly increased ketamine's appeal as a novel antidepressant. Consequently, many ketamine infusion clinics have been established in Africa. However, there is little regulation or guidance for ketamine infusions. Furthermore, while esketamine is expensive and hence inaccessible to a large portion of the African population, racemic ketamine is significantly cheaper and has demonstrated clinical potential. However, there is currently a limited understanding of the neurological mechanisms of action of racemic ketamine in treating and managing depression, especially in a diverse African population. Therefore, this review aims to provide an African context of depression and the therapeutic potential of ketamine by highlighting aspects of its molecular mechanism of action.
RESUMEN
Hypothalamic-pituitary-adrenal (HPA) axis dysregulation is linked to the pathophysiology of depression. Although exogenous adrenocorticotropic hormone (ACTH) is associated with a depressive-like phenotype in rodents, comprehensive neurobehavioral and mechanistic evidence to support these findings are limited. Sprague-Dawley rats (male, n = 30; female, n = 10) were randomly assigned to the control (male, n = 10) or ACTH (male, n = 20; female n = 10) groups that received saline (0.1 ml, sc.) or ACTH (100 µg/day, sc.), respectively, for two weeks. Thereafter, rats in the ACTH group were subdivided to receive ACTH plus saline (ACTH_S; male, n = 10; female, n = 5; 0.2 ml, ip.) or ACTH plus imipramine (ACTH_I; male, n = 10; female, n = 5;10 mg/kg, ip.) for a further four weeks. Neurobehavioral changes were assessed using the forced swim test (FST), the sucrose preference test (SPT), and the open field test (OFT). Following termination, the brain regional mRNA expression of BDNF and CREB was determined using RT-PCR. After two-weeks, ACTH administration significantly increased immobility in the FST (p = 0.03), decreased interaction with the center of the OFT (p < 0.01), and increased sucrose consumption (p = 0.03) in male, but not female rats. ACTH administration significantly increased the expression of BDNF in the hippocampus and CREB in all brain regions in males (p < 0.05), but not in female rats. Imipramine treatment did not ameliorate these ACTH-induced neurobehavioral or molecular changes. In conclusion, ACTH administration resulted in a sex-specific onset of depressive-like symptoms and changes in brain regional expression of neurotrophic factors. These results suggest sex-specific mechanisms underlying the development of depressive-like behavior in a model of ACTH-induced HPA axis dysregulation.
