Anticonvulsive effects of the dopamine agonist lisuride maleate after experimental traumatic brain injury

Department of Neurosurgery, University Hospital Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.
Neuroscience Letters (Impact Factor: 2.03). 02/2010; 470(2):150-4. DOI: 10.1016/j.neulet.2009.12.075
Source: PubMed


Traumatic brain injury is a heterogeneous disease, encompassing a wide range of pathologies. The dopamine agonist lisuride is well established in the therapy of Parkinson's disease. Additionally to its dopaminergic effects it decreases prolactine release, reducing the amount of inflammatory mediators such as TNF-alpha or Il-6. Lisuride has strong binding affinity to serotonergic and histaminergic receptors on neuronal and glial cells leading to scavenging of highly reactive free radicals. Due to its interaction with dopaminergic D2 and D4 receptors as well as 5-HT-1A receptors, NMDA-receptor signaling and glutamate-mediated excitotoxicity can be modulated beneficially. Despite of these promising neuroprotective effects, experimental data scrutinizing the effects of lisuride after acute brain injury are sparse. We therefore investigated the effect of lisuride after controlled cortical impact injury (CCII) in rats. 70 male Sprague-Dawley rats were randomized to lisuride or to placebo treatment by an initial s.c. loading dose (0.3mg/kg BW) and following continuous application (0.5mg/kg/d) by s.c. implanted osmotic pumps. In three experimental groups we determined (sub)acute neuro-physiological changes after trauma. Mean arterial blood pressure, intracranial pressure, and electrical brain activity were monitored acutely for up to 3h after trauma. Brain edema formation was assessed 24h after CCII. Furthermore, contusion volumes were quantified by magnetic resonance tomography and neurological testing was performed for up to 7 days after injury. Associated with the administration of lisuride there was a significant reduction in duration and number of post-traumatic seizures. Despite of a sustained arterial hypotension following the initial bolus administration in the treatment group, contusion volumes and neurological function tests did not differ significantly in comparison to the control group. Overall, lisuride seems to have significant anticonvulsive effects but seems not to influence secondary brain damage in this experimental model.

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    • "These observations definitely prompt for a better investigation of the anti-epileptogenic efficacy of D2R-selective agonists. Indeed, different D2R agonists (including bromocriptine) have neuroprotective efficacy against KA-induced brain damage (Micale et al., 2006), and recent studies promisingly show that lisuride may reduce seizures occurring after traumatic brain injury (Zweckberger et al., 2010). Further investigation in both animal models and clinical settings is needed to establish the anti-epileptogenic efficacy of D2R agonists. "
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    ABSTRACT: After traumatic brain injury (TBI), the primary insult is followed by a cascade of secondary events which lead to enlargement of the primary lesion and are potentially amenable to therapeutic intervention. Lisuride is a dopaminergic agonist with additional serotoninergic, adrenergic, and glutamate antagonistic properties. In lack of previous data on lisuride in TBI, and based on well documented changes of dopamine metabolism after TBI, we speculated that lisuride could provide neuroprotection in the acute and post-acute stage of controlled cortical impact (CCI) injury in rats. The effect of varying dosages of lisuride on physiological parameter was investigated. Cerebral microdialysis (CMD) was employed to provide a temporal profile of lactate, pyruvate, glucose and glutamate in the pericontusional brain tissue. Additionally, brain edema formation and the development of contusion volume were assessed. In this study, no effect of treatment was seen on physiological parameters or microdialysis profiling of tissue metabolites. Whereas posttraumatic increase in brain water content and an increase in contusion volume could be observed, there was no significant effect of treatment. Taken together, our results suggest that lisuride does not provide neuroprotection in the CCI model at the acute and subacute stages. Based on the available literature, however, it might be possible that dopamine agonists such as lisuride, respectively, improve outcome in terms of cognitive function in a chronic setting.
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