The single versus combinatorial effects of MK-801, CNQX, Nifedipine and AP-3 on primary cultures of cerebellar granule cells in an oxygen-glucose deprivation model

Vol. 55 No. 3 Suppl., 2014
This supplement was not sponsored by Outside Organizations.


Ana-Maria Zagrean, Ana Spataru, Mihai Ceanga, Leon Zagrean

The excitotoxicity cascade associated with energetic failure during and after cerebral ischemia involves the overactivation of glutamate receptors and intracellular calcium loading. We searched for synergistic neuroprotective effects of various drugs designed to prevent intracellular calcium influx in a model of oxygen-glucose deprivation (OGD) in cerebellar granule cells primary cultures. (5S,10R)-(-)-5-Methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine hydrogen maleate (MK-801), D,L-2-Amino-3-phosphonopropionic acid (AP-3), 6-Cyano-7-nitroquinoxaline-2,3-dione disodium salt (CNQX) and Nifedipine were tested alone or in combinations. Treatments were applied during a two-hour OGD exposure and cellular outcome was assessed throughout 20-hour reoxygenation by the measurement of Propidium Iodide (PI) fluorescence. All treatments were able to prevent neuronal damage. OGD resulted in a mortality of 36.3+/-2.3% and 61.3+/-3.1% after 10 and 20 hours of reoxygenation, respectively. The most effective single treatment was AP-3 (3.3+/-1.4%; 17.9+/-2.6% mortality after 10 and 20 hours), followed in order by Nifedipine (7.2+/-1.6%; 20.1+/-3.0%), CNQX (8.5+/-2.5%; 20.0+/-3.5%), and MK-801 (14.9+/-2.6%; 39.3+/-6.4%). The combination of AP-3 with MK-801 showed a moderate synergistic effect (11.8+/-2.0% mortality at 20 hours), while the combinations of CNQX with Nifedipine and CNQX with MK-801, as well as the triple mix CNQX, Nifedipine and MK-801 failed to show a further improvement in the reduction of cellular death. In conclusion, targeting two mechanisms of cellular demise (ionotropic receptors and metabotropic glutamate receptors) provided an advantage against several unimodal strategies (blocking calcium entry through ionotropic glutamate receptors and L-type calcium channels). Our results suggest that a multimodal combinatorial treatment strategy in cerebral ischemia may increase neuroprotective efficacy and call for further research.

Corresponding author: Ana-Maria Zagrean, Associate Professor, MD, PhD; e-mail:,

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Iulia Alecsandra Salcianu, Ana Magdalena Bratu, Simona Bondari, Camelia Dobrea, Andrei Colita, Constantin Zaharia, Dan Bondari

Bone marrow edema (BME) is defined as an excess of fluids that builds up in the bone marrow (BM), commonly found because of osteoporosis, trauma, infections, ischemia or neoplasia. Histologically, BME is characterized by accumulation of extracellular eosinophilic fluid. Magnetic Resonance Imaging (MRI) is the only method that highlights the presence of BME caused by various diseases, including the one associated with hematological malignancies. The classic MRI protocol for the study of BM and BME includes T1- and T2-weighted sequences, the STIR sequence, and in some cases, the administration of intravenous contrast agents in T1-weighted sequences. Fifty-four patients were investigated; there were identified 30 patients with MRI features of BME. Out of the 30 patients with BME, 24 were known to have a malignant hematological disease (multiple myeloma, leukemia, lymphoma); for the remaining subjects, imagistic findings and other laboratory investigations led to multiple myeloma diagnosis. Of the 30 patients, six showed characteristic lesions of the underlying disease as well as BME; four patients had only BME. BM is a structure that is commonly investigated using MRI scans, regardless of the examined bone segment. T1-weighted images and T2-weighted with fat suppression are essential for BME evaluation. Moreover, MRI allows monitoring disease progression and treatment response in patients with malignant hemopathies.

Corresponding author: Iulia Alecsandra Salcianu, MD; e-mail:

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