Irene Gerlach

Upregulation of ICAM-1 and MCP-1 but not of MIP-2 and sensorimotor deficit in response to traumatic axonal injury in rats.

The pathophysiology of traumatic axonal injury (TAI) is only partially understood. In this study, we investigated the inflammatory response as well as the extent of neurological deficit in a rat model of traumatic brain injury (TBI). Forty‐two adult rats were subjected to moderate impact‐acceleration brain injury and their brains were analyzed immunohistochemically for ICAM‐1 expression and neutrophil infiltration from 1 hr up to 14 days after trauma. In addition, the chemotactic factors MIP‐2 and MCP‐1 were measured in brain homogenates by ELISA. For evaluating the neurological deficit, three sensorimotor tests were applied for the first time in this model. In the first 24 hr after trauma, the number of ICAM‐1 positive vessels increased up to 4‐fold in cortical and subcortical regions compared with sham operated controls (P < 0.05). Maximal ICAM‐1 expression (up to 8‐fold increase) was detected after 4 days (P < 0.001 vs. 24 hr), returning to control levels in all brain regions by 7 days after trauma. MCP‐1 was elevated between 4 hr and 16 hr post‐injury as compared with controls. In contrast, neither neutrophil infiltration nor elevation of MIP‐2, both events relevant in focal brain injury, could be detected. In all neurological tests, a significant deficit was observed in traumatized rats as compared with sham operated animals from Day 1 post‐injury (grasping reflex of the hindpaws: P < 0.001, vibrissae‐evoked forelimb placing: P = 0.002, lateral stepping: P = 0.037). In conclusion, after moderate impact acceleration brain injury ICAM‐1 upregulation has been demonstrated in the absence of neutrophil infiltration and is paralleled by a selective induction of chemokines, pointing out that individual and distinct inflammatory events occur after diffuse vs. focal TBI. J. Neurosci. Res. 63:438–446, 2001.

5-HT1A receptor agonist-mediated protection from MPTP toxicity in mouse and macaque models of Parkinson's disease

Excitotoxicity-mediated cell death is involved in Parkinsons disease (PD). 5-HT1A receptor agonists can protect from such mechanisms. The current study demonstrates that the 5-HT1A agonists BAY 639044 and repinotan have neuroprotective effects in a subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. In addition, we also show that both compounds delay the appearance of parkinsonian motor abnormalities in a MPTP monkey model that recapitulates the progressive nature of PD. Thus, BAY 639044 or repinotan treatment was initiated when there was 30% neuronal death in the substantia nigra pars compacta, and nerve terminal loss in the striatum was 40%, i.e., compatible with the clinical situation where early symptomatic patients would receive such a treatment. The delay in appearance of parkinsonian motor abnormalities is a consequence of partial neuroprotection of nigrostriatal dopamine neurons, both at neuronal and terminal levels as shown for BAY 639044. These results suggest that 5-HT1A agonists, such as BAY 639044, may protect from neurodegeneration and delay the worsening of motor symptoms in Parkinson patients.

Effects of subdural haematoma on sensorimotor functioning and spatial learning in rats

Twenty per cent of all strokes are haemorrhagic in character and are associated with severe disturbances in sensorimotor behaviour and cognition. Although spontaneous recovery of pre-stroke functioning occurs in some cases, the process is demanding, slow, and often incomplete. A first step in the preclinical testing of new putative, neuroprotective and recovery-supporting therapeutics is to validate animal models of brain injury. In a series of four experiments we evaluated the behavioural impairments and the time course of recovery of functional deficits in rats with an experimentally induced subdural haematoma. We found that unilateral subdural haematoma resulted in dysfunction in both simple reflexive (experiment 1) and skilled sensorimotor behaviour (experiment 2). Reflexive behaviour did not recover, or recovered only marginally, and neither did the deficits in skilled forepaw use. Bilateral subdural haematoma impaired the learning and memory performance of adult (experiment 3) and old rats (experiment 4) in the Morris water escape task. Considering the diversity of the deficits found in our experiments, we conclude that different models are needed to cover the broad range of deficits seen in stroke patients.

The effects of subdural haematoma on spatial learning in the rat

Although memory deficits are one of the most persistent consequences of human subdural haematoma, cognitive functioning has hardly been investigated in the rat subdural haematoma model. In the present study, the effects on spatial learning of right- and left-sided unilateral subdural haematoma and of bilateral subdural haematoma induced above the sensorimotor cortical areas were evaluated. Spatial learning was assessed by standard acquisition in the Morris water escape task (five sessions). Additional issues addressed were sensorimotor functioning (footprint analysis), recovery of cognitive functioning (tested by an overtraining and a reversal training) and replicability of induced cognitive deficits. Following unilateral subdural haematoma surgery, hardly any impairments in the Morris water escape task were observed: rats with a unilateral right-sided subdural haematoma showed very mild, transient deficits, whereas rats with left-sided subdural haematoma were indistinguishable from controls. Bilateral subdural haematoma surgery led to a clear, although transient, performance deficit. We conclude that animals with bilateral subdural haematoma may provide a promising cognitive deficit model for investigating recovery of function.