Combination therapy in ischemic stroke: synergistic neuroprotective effects of memantine and clenbuterol.
OBJECTIVE
Although excitotoxic overactivation of glutamate receptors has been identified as a major mechanism of ischemic brain damage, glutamate receptor antagonists failed in stroke trials, in most cases because of limited therapeutic windows or severe adverse effects. Therefore, we chose memantine and clenbuterol, both approved safe and efficient in their respective therapeutical categories, and examined combinations of these neuroprotectants for possible therapeutic interactions in ischemic stroke.


METHODS
Combinations of the N-methyl-D-aspartate (NMDA) receptor antagonist memantine (20 mg/kg) with the beta2-adrenoceptor agonist clenbuterol (0.3 to 3 mg/kg) were tested in a mouse model of permanent focal cerebral ischemia. In addition, combinations of memantine (1 to 10 nmol/L) and clenbuterol (1 to 10 nmol/L) were examined in cultured hippocampal neurons exposed to glutamate (500 micromol/L) or staurosporine (200 nmol/L).


RESULTS
The infarct size was further reduced by combination therapy as compared with effects of the respective neuroprotectants alone. Of note, in combination with memantine, the therapeutic window of clenbuterol was significantly prolonged up to 2 hours after ischemia. Experiments in postnatal cultures of rat hippocampal neurons exposed to glutamate or staurosporine confirmed that neuroprotection by combinations of memantine and clenbuterol exceeded the effects of the individual compounds.


CONCLUSIONS
Combinations of memantine with clenbuterol extend the respective therapeutic window and provide synergistic cerebroprotective effects after stroke.
Culmsee
Carsten
C
Institut für Pharmakologie und Toxikologie, Philipps-Universität, Marburg, Germany. ccuph@cup.uni-muenchen.de
Junker
Vera
V
Kremers
Wolfram
W
Thal
Serge
S
Plesnila
Nikolaus
N
Krieglstein
Josef
J
D000318:Adrenergic beta-Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D002478:Cells, Cultured; D002976:Clenbuterol / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D005971:Glutamates / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D008559:Memantine / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D019311:Staurosporine / Q000494:pharmacology; D020521:Stroke / Q000188:drug therapy*
D000318:Adrenergic beta-Agonists; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D019311:Staurosporine; D008559:Memantine; D002976:Clenbuterol