Thalidomide and Phosphodiesterase 4 Inhibitors as Host Directed Therapeutics for Tuberculous Meningitis: Insights From the Rabbit Model

Abstract

Tuberculous meningitis (TBM) is the most devastating form of extrapulmonary Mycobacterium tuberculosis infection in humans. Severe inflammation and extensive tissue damage drive the morbidity and mortality of this manifestation of tuberculosis (TB). Antibiotic treatment is ineffective at curing TBM due to variable and incomplete drug penetration across the blood-brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barriers. Adjunctive corticosteroid therapy, used to dampen the inflammation, and the pathologic manifestation of TBM, improves overall survival but does not entirely prevent the morbidity of the disease and has significant toxicities, including immune-suppression. The rabbit has served as a fit for purpose experimental model of human TBM since the early 1900s due to the similarity in the developmental processes of the brain, including neuronal development, myelination, and microglial functions between humans and rabbits. Consistent with the observations made in humans, proinflammatory cytokines, including TNF-α, play a critical role in the pathogenesis of TBM in rabbits focusing the attention on the utility of TNF-α inhibitors in treating the disease. Thalidomide, an inhibitor of monocyte-derived TNF-α, was evaluated in the rabbit model of TBM and shown to improve survival and reduce inflammation of the brain and the meninges. Clinical studies in humans have also shown a beneficial response to thalidomide. However, the teratogenicity and T-cell activation function of the drug limit the use of thalidomide in the clinic. Thus, new drugs with more selective anti-inflammatory properties and a better safety profile are being developed. Some of these candidate drugs, such as phosphodiesterase-4 inhibitors, have been shown to reduce the morbidity and increase the survival of rabbits with TBM. Future studies are needed to assess the beneficial effects of these drugs for their potential to improve the current treatment strategy for TBM in humans.

Keywords: cerebrospinal fluid; corticosteroid; inflammation; mycobacterium; phosphodiesterase-4 inhibitors; tuberculosis; tumor necrosis factor-alpha.

Figure 1

(A) Timeline of rabbit model TBM development. The first experimental model of rabbit TBM was established in 1923 using intra-cisternal inoculation of pathogenic mycobacteria. This model shows the presence of Mycobacteria in the meninges (Rich foci), disease progression with various infection/inoculum doses of different mycobacterial strains (chronic and subacute TBM) and the efficacy of anti-inflammatory drugs, such as thalidomide, on TBM. Since the TBM has a high mortality rate among children, a pediatric model of rabbit TBM was also developed and evaluated for disease progression in this population. Recent developments with the rabbit TBM model have introduced imaging techniques, such as PET scan (¹²⁴I-DPA-713), which is vital in understanding host-drug interactions during TBM treatment. (B) Disease presentation in rabbit model of TBM. The rabbit model of TBM have used different strains of pathogenic Mycobacterium, which demonstrated heterogeneity in the outcome of infection. High- and low-inoculum doses differ in their onset of disease symptoms and the rate of progression of infection. The laboratory Mtb strain H37Rv, clinical Mtb isolate HN878 and a high dose M. bovis Ravenal infection led to elevated cytokine response and severe inflammation of the meninges. These animals had early and robust disease pathology, accompanied by the presence of necrotizing granulomas and dissemination of Mtb to other organs of the body. In contrast, infection by Mtb CDC1551 and a low-dose M. bovis Ravenal, displayed a delayed and moderate-to-low inflammatory response without bacillary dissemination to other organs of the infected animals.

Figure 2

Potential mode of action of thalidomide and its derivatives in regulating host inflammatory response. IMiDs and SelCiDs are derivatives of thalidomide with anti-inflammatory properties. However, compounds of these two classes of anti-inflammatory agents function differentially as shown. Red arrow indicates down-regulation and green arrow indicate up-regulation. θ indicates inhibition of the pathway.