7-Nitroindazole, but Not Aminoguanidine, Attenuates the Acute Inflammatory Responses and Brain Injury during the Early Phase of <i>Escherichia coli</i> Meningitis in the Newborn Piglet

Abstract

We evaluated the anti-inflammatory and neuroprotective effects of the selective neuronal nitric oxide synthase inhibitor 7-nitroindazole and aminoguanidine, which predominantly inhibits inducible nitric oxide synthase, during the early phase of experimental bacterial meningitis in the newborn piglet. Meningitis was induced by intracisternal injection of 10⁸ colony-forming units of Escherichia coli in 100 µl of saline. 7-Nitroindazole significantly attenuated the meningitis-induced acute inflammatory responses such as increased intracranial pressure, decreased cerebrospinal fluid (CSF) glucose concentration, and CSF leukocytosis at 2 h. However, meningitis-induced CSF leukocytosis at 4 h and increased CSF lactate and tumor necrosis factor alpha levels were not significantly attenuated. Reduced cerebral cortical cell membrane Na⁺,K⁺-ATPase activity and increased lipid peroxidation products, indicative of meningitis-induced brain cell membrane dysfunction, were also significantly improved with 7-nitroindazole treatment. In contrast, although aminoguanidine significantly attenuated the increase in the CSF tumor necrosis factor alpha level, it failed to attenuate the acute inflammation and the ensuing brain injury in bacterial meningitis. In summary, 7-nitroindazole, but not aminoguanidine, significantly attenuated the acute inflammatory responses and brain injury during the early phase of neonatal bacterial meningitis.

Inhibition of neuronal nitric oxide synthase by 7-nitroindazole attenuates acute lung injury in an ovine model

“…It has also reported that ϳ40% of exhaled NO is derived from nNOS in mice (7). Inhibition of nNOS resulted in significant attenuation of acute inflammatory response and brain injury during bacterial meningitis (27). De Sanctis et al (6) demonstrated an important role of nNOS in airway hyperresponsiveness in an allergic asthma model using nNOS knockout mice.…”

Effects of Hypertonic (7%) Saline on Brain Injury in Experimental Escherichia coli Meningitis

“…Although we have observed that the BBB permeability and acute inflammatory responses were directly related to the concentration of the bacteria in the CSF space (33, 34), not to the routes of bacterial entry into the CSF (37), and the BBB permeability to the glucose increased markedly only 1 hr after intracisternal inoculation of bacteria (3) in our previous studies, further studies will be necessary to determine whether the BBB would be more permeable if the infection have occurred through bacteremia rather than direct intracisternal bacterial injection.…”

“…To simulate the clinical situation, HTS was infused 6 hr after induction of meningitis when the acute inflammatory responses reached a maximal level (3, 4, 25, 26), and the animals were sacrificed 4 hr after beginning of HTS infusion because it was the least indispensable but best affordable time period (3, 25, 33, 34, 37) to test the efficacy of HTS as an adjunctive therapy in bacterial meningitis. The trend of any changes observed at 4 hr did not change significantly afterward up to 8 hr in our previous studies of experimental meningitis (4, 26).…”

Increased Na+,K+-ATPase activity in the rat brain after meningitis induction byStreptococcus pneumoniae

“…Earlier studies have shown that Na + ,K + -ATPase activity is altered in ischaemia (18), neurodegenerative diseases (19), with chronic administration of ketamine (20), increased in animal models using lipopolysaccharide (21) and resulted in increased Na + K + pump activity (22) in sepsis also. Furthermore, Na + ,K + -ATPase activity was inhibited by interleukin-1 β (IL-1 β ) in cardiac myocytes (23) and reduced cerebral cortical cell membrane Na + ,K + -ATPase activity in meningitis by Escherichia coli in the newborn piglet (24). According to Sellner et al (25), a problem factor that contributes to this insufficient therapeutic in the meningitis treatment is our deficient understanding of the pathogenesis and pathophysiology of the bacterial infection in the central nervous system.…”