Synergistic effects of prostaglandin E1 and lithium in a rat model of cerebral ischemia¹

Abstract

Aim: Heat shock proteins (HSPs) are important regulators of cellular survival and exert neuroprotective effects against cerebral ischemia. Both prostaglandin E1 (PGE1) and lithium have been reported to protect neurons against ischemic injury. The present study was undertaken to examine if lithium could potentiate the neuroprotection of PGE1 against cerebral ischemia, and if the synergetic effects take place at the level of HSPs. Methods: Brain ischemia was induced by a permanent middle cerebral artery occlusion (pMCAO) in rats. Rats were pretreated with subcutaneous injection of lithium for 2 d and a single intravenous administration of PGE1 immediately after ischemic insult. Cerebrocortical blood flow of each group was closely monitored prior to onset of ischemia, 5 min, 15 min, 30 min and 60 min after surgical operation. Body temperature was measured before, 5 min, 2 h and 24 h after the onset of pMCAO. The infarct volume, brain edema and motor behavior deficits were analyzed 24 h after ischemic insult. Cytoprotective HSP70 and heme oxygenase-1 (HO-1) in the striatum of the ipsilateral hemisphere were detected by immunoblotting. Brain sections from the striatum of the ipsilateral hemisphere were double-labeled with the anti-HSP70 antibody and 4,6-diamidino-2-phenylindole (DAPI). Results: Treatment with PGE1 (8 and 16 µg/kg, iv) or lithium (0.5 mEq/kg, sc) alone reduced infarct volume, neurological deficits and brain edema induced by focal cerebral ischemia in rats. Moreover, a greater neuroprotection was observed when PGE1 and lithium were given together. Co-administration of PGE1 and lithium significantly upregulated cytoprotective HSP70 and HO-1 protein levels. Conclusion: Lithium and PGE1 may exert synergistic effects in treatment of cerebral ischemia and thus may have potential clinical value for the treatment of stroke.

Combined prostaglandin E1 and lithium exert potent neuroprotection in a rat model of cerebral ischemia

“…In the groups treated with PGE1 or lithium alone, a reduction in infarct volume and improvement of neurological deficits was observed, but a greater reduction in infarct volume and neurological deficits was seen in rats that were given a PGE1(S)+Li mixture (PGE1 22.6 nmol/kg+Li 0.5 mmol/kg). These results suggest that the PGE1+Li mixture might mimic the synergistic combination therapy of PGE1 and lithium reported in the previous study [14] . The suitable molar ratio of PGE1 to lithium for the PGE1+Li mixture was about 4.5×10 -5 :1.…”

“…Previous work showed that neither PGE1 alone nor a combination of PGE1 with lithium influences the cerebrocortical blood flow of the pMCAO animals [14] . The results in this study were similar.…”

“…In previous research from our laboratory [14,37] , lithium potentiated the neuroprotective effects of PGA1 and PGE1 through the upregulation of HSPs. However, PGA1 could only be delivered through intracerebral ventricle administration [37] , which is not a viable delivery route in clinics.…”

“…After the pMCAO operation, the rCBF sharply dropped to approximately 5%-10% of the preischemia value. Then the rCBF was measured again 5, 10, 15, 30, 60, and 120 min after drug administration [14] . Body temperature was closely monitored with a rectal probe and maintained in the range of 37.0±0.5 °C with a heating pad (Institute of Biomedical Engineering, CAMS, BME-412A ANIMAL REGULATOR) during and after surgery until the animals recovered from the anesthesia.…”

“…In a previous study, research from our laboratory [14] found that lithium could potentiate the neuroprotective effects of PGE1 through synergistic induction of HSPs, but the differCombined prostaglandin E1 and lithium exert potent neuroprotection in a rat model of cerebral ischemia www.nature.com/aps Sheng R et al Acta Pharmacologica Sinica npg ent administration routes of PGE1 (intravenous injection, iv) and lithium (subcutaneous injection, sc) make the clinical administration of drug combination inconvenient. Therefore, in the present study, we formulated a PGE1+Li mixture for intravenous administration.…”