Influence of monosialoganglioside inner ester on neurologic recovery after global cerebral ischemia in monkeys.

Abstract

We assessed the consequences of transitory global cerebral ischemia and the influence of monosialoganglioside inner ester (AGF 2) treatment on neurologic outcome, cerebral blood flow, and cerebral metabolic rate in monkeys over 48 hours. Global cerebral ischemia was produced by a cervical tourniquet and a lowering of blood pressure to 6.65 kPa; recirculation followed after 30 minutes. AGF 2 (30 mg/kg) was administered intravenously immediately after initiation of recirculation and intramuscularly twice a day for 48 hours. Our results show that treatment with AGF 2 significantly accelerated the rate of neurologic recovery. Improvement was evident 5 hours after ischemia; full neurologic recovery was observed in half of the monkeys 48 hours after ischemia. This recovery was associated with a less severe reduction in cerebral blood flow without a concomitant increase in the cerebral metabolic rate. (Stroke 1989; 20:652-656) G angliosides are sialic acid-containing glycosphingolipids with particular abundance in the outer membrane surface of neuronal cells.' Although their biologic function is still largely obscure, considerable evidence now indicates that systemically administered gangliosides are effective in improving the outcome following neuronal injury to adult rodents. In the initial work of Ceccarelli et al, 2 a mixture of bovine brain gangliosides enhanced recovery of the denervated cat nictitating membrane, an effect most probably associated with an enhanced rate of axonal regrowth.3 Subsequently, the monosialoganglioside GM 1 (nomenclature according to Svennerholm 4 ) alone was found to affect recovery following injury to the central nervous system (CNS). For example, following partial unilateral hemitransection of the nigrostriatal pathway, chronically administered GM 1 facilitated the recovery of dopaminergic synaptic function in the lesioned striatum.5 This effect was associated with both enhanced survival of nigral dopaminergic cell bodies and with the associated reduction of the imbalance in energy metabolism and blood flow between the striata of the lesioned and unlesioned sides. Received March 4, 1988; accepted October 18, 1988. GM 1 effects have also been detected during the acute phase following brain insults, including cerebral ischemia. GM 1 treatment has been shown to have beneficial effects following both transitory middle cerebral artery occlusion in cats and permanent unilateral ligation of the common carotid artery in gerbils. -9We describe the effects of AGF 2, the inner ester derivative of GM 1, following transitory global cerebral ischemia in monkeys. We used AGF 2 because of its reportedly greater ability to penetrate the blood-brain barrier. 10 Materials and MethodsWe used 27 cynomolgus monkeys {Macaca fascicularis) of either sex weighing 3-6 kg. Anesthesia was induced with 3 mg/kg i.m. ketamine hydrochloride followed by an intravenous perfusion of 25 mg/kg chloralose. The monkeys were intubated and then ventilated (Delhomme, Bird Mark 8, Paris, France) so as to maintain Pacc>2 at 5...

Temporal changes in edema, Na+, K+, and Ca++ in focal cortical stroke: GM1 ganglioside reduces ischemic injury

“…Our laboratories previously reported that acute GM 1 treatment significantly reduced mortality and injury in global ischemia (Karpiak et al, 1987a;Mahadik et al , 1988). Subsequently, others have reported that GMl is effective in reducing CNS ischemic injury (Cahn et al, 1989;KOmatsumoto et al, 1988;Urbanics et al, 1989;Mazzari et al, 1990;Skaper et al, 1989). Recent clinical studies support the efficacy of ganglioside treatment for CNS ischemia (Argentino et al, 1989).…”

GM1 Ganglioside treatment after global ischemia protects changes in membrane fatty acids and properties of Na+, K+‐ATPase and Mg2+‐ATPase

“…Beneficial effects of gangliosides have been reported in other animal models of ischemia Cahn et al, 1986Cahn et al, , 1989Karpiak et al, 1987Karpiak and Mahadik, 1990;Bharucha et al, 1989) and in stroke patients (Bassi et al, 1986;Argentino et al, 1989;Karpiak and Mahadik, 1990). We have hypothesized that these effects are due to a protection of plasma membrane function through stabilization of its structural integrity.…”

“…This relationship between GMl and trophic factors is noteworthy since it has been suggested that Na + ,K + -ATPase losses in damaged neurons are protected by NGF (Demediuk et al, 1985;Sendtner et al, 1988). Lastly, there are reports that GMl acutely affects cerebral blood flow (CBF) reperfusion after arterial occlusion (Greenberg et al, 1986;Cahn et al, 1986Cahn et al, , 1989. This hypothesis is notable, since GM1 is Shawn to protect the CNS cholinergic system (Maysinger et al, 1988;Cuello et al, 1989), which has been implicated in the regulation of CBF (Scremin and Scremin, 1986).…”

Protective effects of a monosialoganglioside derivative following transitory forebrain ischemia in rats.

“…10 The molecular mechanisms underlying the capability of siagoside to limit neuronal damage after a cerebral hypoxic/ischemic insult remain to be fully denned. When added to cultured neuronal cells, monosialogangliosides are stably incorporated into the outer layer of the cell membrane in a temperature-, time-, and concentration-dependent manner.…”