Tuberculosis (TB) is a chronic infectious disease in which prolonged, non-resolutive inflammation of the lung may lead to metabolic and neuroendocrine dysfunction. Previous studies have reported that individuals coursing pulmonary TB experience cognitive or behavioural changes; however, the pathogenic substrate of such manifestations have remained unknown. Here, using a mouse model of progressive pulmonary TB, we report that, even in the absence of brain infection, TB is associated with marked increased synthesis of both inflammatory and anti-inflammatory cytokines in discrete brain areas such as the hypothalamus, the hippocampal formation and cerebellum accompanied by substantial changes in the synthesis of neurotransmitters. Moreover, histopathological findings of neurodegeneration and neuronal death were found as infection progressed with activation of p38, JNK and reduction in the BDNF levels. Finally, we perform behavioural analysis in infected mice throughout the infection, and our data show that the cytokine and neurochemical changes were associated with a marked onset of cognitive impairment as well as depressive- and anxiety-like behaviour. Altogether, our results suggest that besides pulmonary damage, TB is accompanied by an extensive neuroinflammatory and neurodegenerative state which explains some of the behavioural abnormalities found in TB patients.

Tuberculosis (TB) is one of the ten leading causes of death worldwide. Patients with TB have been observed to suffer from depression and anxiety linked to social variables. Previous experiments found that the substantial pulmonary inflammation associated with TB causes neuroinflammation, neuronal death, and behavioral impairments in the absence of brain infection. Curcumin (CUR) is a natural product with antioxidant, anti-inflammatory and antibacterial activities. In this work, we evaluated the CUR effect on the growth control of mycobacteria in the lungs and the anti-inflammatory effect in the brain using a model of progressive pulmonary TB in BALB/c mice infected with drug-sensitive mycobacteria (strain H37Rv). The results have shown that CUR decreased lung bacilli load and pneumonia of infected animals. Finally, CUR significantly decreased neuroinflammation (expression of TNF$\mathsf{\alpha }$, IFN$\mathsf{\gamma }$ and IL12) and slightly increased the levels of nuclear factor erythroid 2-related to factor 2 (Nrf2) and the brain-derived neurotrophic factor (BDNF) levels, improving behavioral status. These results suggest that CUR has a bactericidal effect and can control pulmonary mycobacterial infection and reduce neuroinflammation. It seems that CUR has a promising potential as adjuvant therapy in TB treatment.

Background During the development of chronic peripheral inflammation, there is a complex activity of specific brain areas that produce neuronal activation and changes in the synthesis, production and activity of neurotransmitters and cytokines. These changes produced afferent responses that contribute to the regulation of inflammatory and immune responses but may also affect the neuropsicoaffective functions, such as learning ability, memory and mood. Pulmonary tuberculosis (TB) is an infectious disease that induces chronic inflammation, so it could produce these neural and immune changes that may occur in the absence of brain infection. In the present study, we determined the immune response in the Central Nervous System (CNS), in a murine model of pulmonary TB and its relationship with the neurotransmitters levels and behavioural abnormalities without brain infection. Methods Using a murine model of pulmonary TB, we studied the synthesis of cytokines by RT-PCR and IHC, the concentrations of the neurotransmitters by HPLC along with neuronal changes and the histopathology alterations within specific brain areas. Different behavioural tests were performed, which include the study of sickness behaviour, anxiety-like behaviour, neurological severity score, short and long-term memory and depression-like behaviour. We evaluated the activation of JNK and p38 and BNDF levels by Western blot. Data were analysed by Two-Way ANOVA, followed by Sidak tests. Results Pulmonary infected male animals showed a brain increased expression of the pro-inflammatory (TNFa, IFNg, IL-12) and anti-inflammatory (IL10, IL4 and TGFb) cytokines, as well as the enzymes indolamine 2-3 dioxygenase (IDO) and induced nitric oxide synthase (iNOS) in the hypothalamus, hippocampus and cerebellum; in coexistence with substantial cha nges in the production of the neurotransmitters norepinephrine, epinephrine, dopamine and serotonin. Neurodegenerative changes occurred in the early stage of the disease, and it led to neuronal death during advanced TB, with activation of p38, JNK and decrease of the BDNF levels. All these changes occurred with sickness behaviour, depressive-like and anxiety-like behaviour, neurological damage and impairment of both short and long-term memory. Conclusions Pulmonary TB produced a neuroinflammatory state and neuronal damage, which evoked several behaviour abnormalities that resembled depression/anxiety states and aroused the interest to control neuroinflammation in TB patients with neuropsychiatric abnormalities.

Tuberculosis (TB) is an important infectious disease and a public health problem. The organs most frequently affected by TB are the lungs; despite this, it has been reported that TB patients suffer from depression and anxiety, which have been attributed to social factors. In previous experimental work, we observed that the extensive pulmonary inflammation characteristic of TB with high cytokine production induces neuroinflammation, neuronal death and behavioral abnormalities in the absence of brain infection. The objective of the present work was to reduce this neuroinflammation and avoid the psycho-affective disorders showed during pulmonary TB. Glucocorticoids (GCs) are the first-line treatment for neuroinflammation; however, their systemic administration generates various side effects, mostly aggravating pulmonary TB due to immunosuppression of cellular immunity. Intranasal administration is a route that allows drugs to be released directly in the brain through the olfactory nerve, reducing their doses and side effects. In the present work, dexamethasone’s (DEX) intranasal administration was evaluated in TB BALB /c mice comparing three different doses (0.05, 0.25 and 2.5 mg/kg BW) on lung disease evolution, neuroinflammation and behavioral alterations. Low doses of dexamethasone significantly decreased neuroinflammation, improving behavioral status without aggravating lung disease.

Fluoride exposure harms human health. Additionally, recent attention has focused on understanding the impact of an adverse in utero environment on the programming of chronic kidney disease in adult offspring. A previous study has described that fluoride alters kidney development, inducing oligonephronia and promoting the premature maturation of remnant nephrons. Therefore, it is essential to continue researching the potential mechanisms involved in fluoride-induced alterations. Female Wistar rats were administered two doses of fluoride (2.5 or 5.0 mg/kg body weight/day) for 20 days before and after mating. The results showed that fluoride diminished catalase and superoxide dismutase activities while increasing the markers of nuclear factor erythroid 2-related factor 2 (Nrf2) activation, mitochondrial dynamics, autophagy, and biogenesis. Morphometric analysis revealed an increase in mitochondrial size and content. Although the levels of Bcl-2-associated X protein (Bax) and B-cell lymphoma 2 (Bcl-2) increased, the activity of caspase-3 and the immunodetection in the TUNEL assay decreased. Several of these changes were mainly observed with the high fluoride dose. In conclusion, the results suggest that fluoride alters the redox status and mitochondrial homeostasis while decreasing apoptosis. It is essential to recognize that, under normal conditions, apoptosis plays a crucial role in proper kidney development, and its occurrence decreases as the structures mature. Therefore, collectively, these alterations could lead to undesirable effects on postnatal life.