Acute and Chronic Acetazolamide Administration in DBA and C57 Mice: Effects of Age

Abstract

The clinical utility of the carbonic anhydrase (CA) inhibitor acetazolamide (ACTZ) is limited because of rapid development of tolerance to its effects. Tolerance is thought to develop as a result of glial cell proliferation and/or increased CA synthesis. DBA mice, susceptible to audiogenic seizures (AGSs) in an age-dependent manner, have increased CA activity as compared with C57 (non-audiogenic seizure susceptible) mice at 21 and 110 days of age. The present work utilized ACTZ to help determine the relationship between increased CA activity in brain and AGSs in DBA mice. Also, minimal electroshock seizure threshold (EST) was measured at various ages in DBA and C57 mice to determine age-related changes in CNS excitability. EST was significantly lower in DBA as compared with C57 mice at 18 days and between 40 and 115 days of age, suggesting that DBA mice remain hyperexcitable to electrical stimulation after they develop resistance to AGSs. ACTZ ED50s against maximal electroshock seizures (MES) were significantly higher in DBA as compared with C57 mice at 26,36, and 115 days of age. This finding correlates with higher CA activity in this strain at 110 days of age, noted previously. However, at 21 days of age, when CA activity is also higher in DBA versus C57 mice, there were no significant differences in ACTZ ED50s against MES between the strains. ACTZ ED50s against AGSs in DBA mice were considerably lower than ACTZ ED50s against MES in either strain, suggesting that a particular fraction of CA is intimately involved in the production of AGSs.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential Susceptibility to Seizures Induced by Systemic Kainic Acid Treatment in Mature DBA/2J and C57BLl6J Mice

“…D2 mice are exquisitely sensitive to soundinduced (audiogenic) seizures until the age of -3 weeks (Hall, 1947). Although D2 mice acquire resistance to audiogenic seizures with maturity, previous work has shown that they remain hyperexcit-able to electrical stimulation throughout adult life (Engstrom et al, 1986). Results of our study confirm that mature D2 mice are more vulnerable than mature B6 mice to induction of behavioral seizures after systemic injection of KA.…”

Induction of New Carbonic Anhydrase II Following Treatment with Acetazolamide in DBA and C57 Mice

“…In CS7 mice, the maximum amount of enzyme per cell at each dose was obtained 24 h after beginning treatment and no further increases were observed with time (Fig. Nevertheless, the persistent increases in CA in DBA mice may explain why they do not become tolerant to the protective effects of acetazolamide on MES (Engstrom et al, 1986). In contrast, the amount of enzymes per cell in DBA mice continued to increase with time and dose up to S days after beginning acetazolamide treatment (Fig.…”

“…Tolerance to protection from MES develops in C57, but not in DBA mice (Engstrom et al, 1986). The elevated quantity of CA in DBA mice, thus, may represent the effects of a functional inhibition of the enzyme.…”

“…DBA mice have a lower electroshock seizure threshold than C57 mice, but protection from MES is achieved with a fourfold higher dose of acetazolamide in DBA than in C57 mice (Engstrom et a!., 1986). Cerebral cortex sections of DBA/2J (audiogenic seizures-susceptible) mice and C57BL/6J (related, nonsusceptible strain) mice were stained with antibody to mouse CA I1 (high-activity isoenzyme) in controls and following treatment with acetazolamide for 1, 3, and 5 days.…”

“…The fluorescent intensity of single cells in the cortex was measured with a fluorescent intensity detector in a fluorescent microscope. DBA mice have a lower electroshock seizure threshold than C57 mice, but protection from MES is achieved with a fourfold higher dose of acetazolamide in DBA than in C57 mice (Engstrom et a!., 1986). Furthermore, tolerance to acetazolamide suppression of MES develops in C57 mice, but not in DBA mice (Engstrom et al, 1986).…”