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Nitric oxide concentrations and cerebrospinal fluid parameters in an experimental animal model of Streptococcus
C J Destache1, C B Pakiz, A K Dash
1Department of Pharmacy Practice, Creighton University School of Pharmacy and Allied Health Professions, Omaha, Nebraska 68178, USA.
Abstract:
Streptococcus pneumoniae is a common cause of meningitis. Nitric oxide (NO) has been implicated in causing cerebral edema. Modulating NO production in cerebrospinal fluid (CSF) may have a role in the treatment of bacterial meningitis. Experimental S. pneumoniae meningitis was induced in a rabbit model to determine CSF parameters and NO concentrations. An electrochemical probe in the CSF throughout the 7-hour experiment monitored NO concentrations. The animals had S. pneumoniae (10(5)) injected intracisternally and incubated for 1 hour. Cerebrospinal fluid 200-300 microl was obtained by intracisternal puncture at zero, 2, 4, and 7 hours after drug administration to measure glucose, protein, and lactic acid by standard chemical methods. White blood cell count was measured by hemocytometry. Three groups of five animals were used-control (C), ceftriaxone (CTX), and ceftriaxone plus dexamethasone (CTX+D). Ceftriaxone concentrations in CSF were obtained by microdialysis and analyzed by high-performance liquid chromatography. Mean (+/- SEM) CSF white blood cell count was significantly higher at 2 hours in the C group than in the other two groups (C 7307 +/- 1302, CTX 605 +/- 345, CTX+D 730 +/- 43/mm3, p<0.002). Ceftriaxone induced a significant rise in protein at 4 hours compared with the other groups (C 364 +/- 107, CTX 1158 +/- 797, CTX+D 365 +/- 100 mg/dl, p<0.02). Cerebrospinal fluid lactic acid was significantly different at 4 and 7 hours between C and CTX+D groups (4-hr C 8.0 +/- 2.2, CTX+D 2.0 +/- 0.4 mmol/L, p<0.05; 7-hr C 10.2 +/- 2.4, CTX+D 2.8 +/- 0.8 mmol/L, p<0.01). Median NO concentrations were significantly elevated in the control group compared with the other two groups (C 11.7, CTX 6.8, CTX+D 6.5 micro, p<0.02 C vs CTX, p<0.01 C vs CTX+D). Average (+/- SEM) NO concentrations were significantly higher in the C group at 4 hours (18.1 +/- 0.4, CTX 5.8 +/- 1.8 microM, p<0.05; CTX+D 11.5 +/- 4.0 microM, p>0.05), whereas they did not rise significantly until 7 hours in the CTX group (CTX 18.7 +/- 0.7, C 8.9 +/- 0.4 microM, p=0.055; CTX+D 8.1 +/- 2.2 microM, p<0.05). These results indicate that ceftriaxone with or without dexamethasone significantly decreases lactic acid concentrations and white cell penetration into the CSF in an experimental model of S. pneumoniae meningitis. In addition, ceftriaxone induced a significant elevation in CSF protein. Median NO production in the CSF was significantly attenuated by ceftriaxone.
Insights
This study shows that ceftriaxone, with or without dexamethasone, reduces white blood cell and lactic acid levels in cerebrospinal fluid during experimental meningitis. Nitric oxide (NO) production was also lowered by ceftriaxone.
Area of Science:
- Neuroscience
- Infectious Diseases
- Pharmacology
Background:
- Bacterial meningitis, particularly from Streptococcus pneumoniae, is a major cause of neurological damage.
- Nitric oxide (NO) is implicated in cerebral edema during meningitis.
- Modulating NO in cerebrospinal fluid (CSF) may offer therapeutic benefits.
Purpose of the Study:
- To investigate the effects of ceftriaxone (CTX) and dexamethasone (D) on CSF parameters and NO concentrations in experimental S. pneumoniae meningitis.
- To evaluate the therapeutic potential of combined CTX and D treatment.
Main Methods:
- Induction of S. pneumoniae meningitis in a rabbit model.
- Monitoring of NO concentrations in CSF using an electrochemical probe.
- Measurement of CSF glucose, protein, lactic acid, and white blood cell counts at various time points.
- Quantification of CSF ceftriaxone concentrations via microdialysis and HPLC.
Main Results:
- CTX and CTX+D significantly reduced CSF white blood cell counts and lactic acid levels compared to controls.
- CTX treatment alone caused a significant increase in CSF protein levels.
- Median NO concentrations were significantly lower in CTX and CTX+D groups compared to controls.
- NO levels rose later in the CTX group than in controls.
Conclusions:
- Ceftriaxone, with or without dexamethasone, effectively reduces inflammation markers (WBC, lactic acid) in experimental bacterial meningitis.
- Ceftriaxone treatment significantly attenuates nitric oxide production in the CSF.
- Further research into combined therapies for bacterial meningitis is warranted.