Doxycycline Reduces Mortality and Injury to the Brain and Cochlea in Experimental Pneumococcal Meningitis

Abstract

Bacterial meningitis is characterized by an inflammatory reaction to the invading pathogens that can ultimately lead to sensorineural hearing loss, permanent brain injury, or death. The matrix metalloproteinases (MMPs) and tumor necrosis factor alpha-converting enzyme (TACE) are key mediators that promote inflammation, blood-brain barrier disruption, and brain injury in bacterial meningitis. Doxycycline is a clinically used antibiotic with anti-inflammatory effects that lead to reduced cytokine release and the inhibition of MMPs. Here, doxycycline inhibited TACE with a 50% inhibitory dose of 74 M in vitro and reduced the amount of tumor necrosis factor alpha released into the cerebrospinal fluid by 90% in vivo. In an infant rat model of pneumococcal meningitis, a single dose of doxycycline (30 mg/kg) given as adjuvant therapy in addition to ceftriaxone 18 h after infection significantly reduced the mortality, the blood-brain barrier disruption, and the extent of cortical brain injury. Adjuvant doxycycline (30 mg/kg given subcutaneously once daily for 4 days) also attenuated hearing loss, as assessed by auditory brainstem response audiometry, and neuronal death in the cochlear spiral ganglion at 3 weeks after infection. Thus, doxycycline, probably as a result of its anti-inflammatory properties, had broad beneficial effects in the brain and the cochlea and improved survival in this model of pneumococcal meningitis in infant rats. Pneumococcal meningitis has a high level of mortality (up to 30%), and brain and/or cochlear damage occurs in up to 50% of the survivors (2). Inflammatory mediators, such as tumor necrosis factor alpha (TNF-␣) and matrix metalloproteinases (MMPs), are produced during the host response to bacteria and contribute to the pathophysiology that can ultimately lead to death, brain damage, and hearing impairment (23,26,29,36). The role of cytokines and MMPs in the pathophysiology of the cochlear damage associated with pneumococcal meningitis is still unknown. However, it has been demonstrated that MMPs are constitutively expressed at high levels in the cochlea (8) and that in meningitis pneumococci and polymorphonuclear leukocytes (PMNs) extend from the cerebrospinal fluid (CSF) to the perilymph via the cochlear aqueduct (5).Tetracyclines are bacteriostatic agents with broad-spectrum antimicrobial activity (3). Doxycycline is a semisynthetic, longacting, second-generation tetracycline which is absorbed rapidly and penetrates well into the brain and CSF (48). Doxycycline has been shown to have anti-inflammatory effects that are separate and distinct from its antimicrobial action (13,16,35,43). These effects include the reduction of cytokine release and the inhibition of MMPs (7, 38). Experimental and clinical studies have indicated that treatment with doxycycline may be beneficial in inflammatory diseases associated with excessive MMP activity (7,13,35).In pneumococcal meningitis massive subarachnoid and ventricular space inflammation is triggered by the presence of bacteria in the CSF space (7,1...

Limited Efficacy of Adjuvant Therapy with Dexamethasone in Preventing Hearing Loss Due to Experimental Pneumococcal Meningitis in the Infant Rat

“…In an adult rat model of PM, the severity of permanent hearing impairment assessed 2 wk after the infection correlated significantly with the loss of type I spiral ganglion neurons (10). We have recently confirmed and expanded the correlation between the loss of type I neurons in the spiral ganglion and the degree of hearing impairment in infant rats (11). Indeed, we have shown that adjuvant therapy with doxcycline combined with ceftriaxone significantly attenuated neuron loss in the spiral ganglion.…”

Doxycycline and HIV Infection Suppress Tuberculosis-induced Matrix Metalloproteinases

“…Therefore, MMPs may represent a potential therapeutic target to limit morbidity and mortality. Doxycycline is a licensed MMP inhibitor in the United States used to treat periodontal disease (30) and has been proposed as an agent to limit pathology in other infectious and inflammatory diseases (31)(32)(33)(34). Doxycycline suppressed multiple MMPs in cellular models (A) 7H11 agar impregnated with doxycycline 2 mg/ml completely suppresses growth of Mtb at 14 days.…”

Neurological Diseases in Relation to the Blood–Brain Barrier

“…Steroids are given to reduce the inflammation and reduce the damage to the eighth nerve. Matrix metalloproteinase inhibitors are also effective in reducing the opening of the BBB and controlling the inflammatory response (Meli et al, 2006).…”