Experimental Pulmonary Tuberculosis in the Absence of Detectable Brain Infection Induces Neuroinflammation and Behavioural Abnormalities in Male BALB/c Mice

Abstract

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.

The Therapeutic Effect of Intranasal Administration of Dexamethasone in Neuroinflammation Induced by Experimental Pulmonary Tuberculosis

“…In previous work we observed that pulmonary infection with M. tb induced sickness behavior, manifested by a significant decrease in body weight and locomotor activity in infected animals [ 33 ]. Sickness behavior is a response related to the inflammatory process.…”

“…Another crucial behavioral change observed in both animals infected with Mtb and TB patients is anxiety. Indeed, we found that lung inflammation generated anxiety-like behaviour in our model of pulmonary TB [ 33 ]. Thus, we evaluated the IN L/DEX and M/DEX treatment’s effect on infected animals that showed anxiety-like behavior using the elevated I-maze [ 34 ], which is a modification of the elevated plus-maze model of anxiety in mice.…”

“…Previously, we observed that pulmonary infection with M. tb induces damage in short-term memory from day 14 post-infection and in long-term memory from day 1 post-infection [ 33 ]. The IN DEX treatment improved the short- and long-term memory in the object recognition test of TB mice ( Figure 5 ).…”

“…We have recently demonstrated neuroinflammation and different neuropsychiatric abnormalities in an experimental model of progressive pulmonary TB without brain infection [ 33 ]. We hypothesize that the GCs intranasal administration could decrease the neuroinflammation in TB mice, and thereby the behavioral abnormalities.…”

A Preliminary Investigation on Plasma Cell Adhesion Molecules Levels by Protein Microarray Technology in Major Depressive Disorder

“…The reason is that CSF is the optimal biological material for examination of molecular status, and has been reported to well reflect the state of the central nervous system (31)(32)(33). Many active substances, such as vascular endothelial growth factor (VEGF), Interleukin (IL)-1, IL-6, and reactive oxygen species (ROS), are closely related to the destruction of the integrity of the bloodbrain barrier (BBB), and these substances are also important members of the pathogenesis of MDD (34). Thus, patients with MDD may have an increase in the permeability of the BBB.…”