Agonists of adenosine A1 receptors have been frequently proposed as candidates for clinical development in treatment of cerebral ischemia and stroke. Numerous experimental studies have shown that pre- and postischemic administration of these drugs results in a very significant reduction of postischemic brain damage. However, only a few studies determined the impact of cerebral ischemia and drug treatment on postischemic recovery of spatial memory. The present paper demonstrates that preischemic i.p. administration of adenosine amine congener (ADAC) at 100 μg/kg in gerbils results in a significant (P < 0.05) reduction of postischemic mortality and hippocampal, cortical and striatal morbidity. Postischemic Morris’ water maze tests show that preischemic treatment with ADAC also leads to a very significant (P < 0.001) reduction of postischemic spatial memory loss. Our results indicate feasibility of further consideration of adenosine A1 receptor agonists as a clinically applicable acute treatment of brain ischemia. Recent development of neuroprotective adenosine A1 receptor agonists that are free of cardiovascular side effects supports such development.

It is known that stimulation of adenosine A1 receptors has a modulatory effect on the excitability of postsynaptic NMDA receptors. Conversely, acute stimulation of NMDA receptors results in release of adenosine via calcium-independent mechanisms. These findings indicate a close functional relationship between these receptors. It is, therefore, possible that chronic, low level stimulation of the NMDA receptor may have a negative impact on these modulatory processes. To investigate this possibility, we have subjected C57BL mice either to an acute injection of a N6-cyclopentyladenosine (CPA, 0.01 mg/kg) or deoxycoformycin (1 mg/kg) followed by a convulsant dose of N-methyl-d-aspartate (NMDA) (60 mg/kg) or to chronic, low level (20 mg/kg i.p. daily) exposure to NMDA for 8 weeks. One day after the last injection of NMDA, animals were injected either with a convulsant dose of NMDA alone, or with either CPA at 0.001 or 0.01 mg/kg, or with 1 mg/kg deoxycoformycin followed 15 min later by 60 mg/kg NMDA. Neither CPA nor deoxycoformycin were protective when NMDA was given acutely at 60 mg/kg. Chronic treatment with NMDA alone or chronic administration of NMDA followed by 0.001 mg/kg CPA had no significant effect on mortality following a convulsant dose of NMDA. However, when the chronic regimen of NMDA was followed by either 0.01 mg/kg CPA or 1 mg/kg deoxycoformycin, mortality was reduced to 10% (CPA), or eliminated completely (deoxycoformycin). Moreover, combination of chronic NMDA treatment with either CPA (both doses) or deoxycoformycin produced a significant improvement in other measures, i.e., seizure onset, intensity of neurological impairment, and extension of time to death. Consonant with these results, apparent density of adenosine A1 receptors was increased in the cortex and hippocampus of animals treated chronically with NMDA. Our results indicate a possible role for NMDA-adenosine A1 receptor interaction in pathologies in which chronic stimulation of the NMDA receptor by endogenous excitatory amino acids may be involved.

Chronic treatment with the selective adenosine A3 receptor agonist N6-(3-iodobenzyl)adenosine-5’-N-methylcarboxamide (IB-MECA) administered prior to either 10 or 20 min forebrain ischemia in gerbils resulted in improved postischemic cerebral blood circulation, survival, and neuronal preservation. Opposite effects, i.e., impaired postischemic blood flow, enhanced mortality, and extensive neuronal destruction in the hippocampus were seen when IB-MECA was given acutely. Neither adenosine A1 nor A2 receptors are involved in these actions. The data indicate that stimulation of adenosine A3 receptors may play an important role in the development of ischemic damage, and that adenosine A3 receptors may offer a new target for therapeutic interventions.

Objective

We hypothesized that fetal folate serum concentrations are lower and placental folate transport is impaired in pregnancies of obese women.

Study Design

Umbilical vein serum and placental tissue were collected from normal weight and obese pregnant women at term. Cellular localization (immunohistochemistry) of Folate Receptor-α (FR-α), Proton Coupled Folate Transporter (PCFT), and Reduced Folate Carrier (RFC) was established. Protein expression (western blot) and transporter activity (isotope labeled methyltetrahydrofolate) were determined in syncytiotrophoblast microvillous membranes (MVM).

Results

Fetal folate concentrations were similar in obese women as compared to normal weight women. Protein expression of FR-α in MVM was increased (+173%), RFC decreased (-41%), and PCFT unchanged. However, activity of FR-α, PCFT, and RFC was unaltered in obesity.

Conclusion

Fetal serum folate concentrations and placental folate transport activity are not altered in obesity at term, suggesting that limited availability of folate does not contribute to abnormal gene methylation and developmental programming.