Introduction

Functional improvement after permanent brain lesions results from changes in the remaining non-affected parts of the brain. The mechanisms involved may vary with post-ischemic time and the type and location of the lesion and can take the form of improved connectivity within individual neurons, modification of cortical representation areas, cortical maps, as well as non-synaptic transmission (Jenkins and Merzenich, 1987; Bach-y-Rita, 1990; Johansson and Grabowski, 1994; Nudo et al., 1996; Buonomano and Merzenich, 1998; Xerri et al., 1998; Nudo, 1999; Johansson, 2000; Hallett, 2001; Hickmott and Merzenich, 2002; Chen et al., 2002a; Keyvani and Schallert, 2002; Frost et al., 2003) There is also increasing evidence that astrocytes take an active part in brain plasticity, not only by their metabolic role and as producers of trophic factors but specifically by playing an active part in neural signaling and in synaptic plasticity (Jones and Greenough, 1996; Chvatal and Sykova, 2000; Araque et al., 2001; Ullian et al., 2001; Mazzanti and Haydon, 2003).

An important question is to what extent post-ischemic events can influence lesion-induced plasticity and improve functional restoration. That neuronal cortical connections can be remodeled was suggested half a century ago (Hebb, 1947). The effect of an activity-stimulating environment on brain function, biochemistry, and morphology has been well documented in the healthy as well as the lesioned brain (Bennett et al., 1964; Rosenzweig, 1966; Volkmar and Greenough, 1972; Will and Kelche, 1992; Kolb, 1995). Housing rats in an enriched environment (i.e. large cages allowing various types of activity) but not including forced training improved outcome after focal brain infarcts induced by proximal or distal ligation of the middle cerebral artery (MCA), even when the transfer to an enriched environment was delayed for 15 days after the arterial occlusion (Ohlsson and Johansson, 1995; Johansson, 1996). This chapter deals, first, with how post-ischemic housing conditions can influence functional outcome, gene expression, neuronal morphology, and interact with specific interventions in rats. Second, the current evidence that blocking neurite inhibitory factors may be a future therapy to promote axonal outgrowth is examined. Finally, current research on endogenous and exogenous neuronal replacement therapy is described and the relevance of animal studies for clinical stroke rehabilitation will be briefly discussed from a personal perspective.

Introduction

There is increasing evidence that functional improvement after permanent brain lesions is related to lesion-induced plasticity in the intact brain. An important question is to what extent postischemic interventions can influence plasticity and functional outcome after brain infarction. We have shown previously that sensorimotor functions improve significantly more in rats that are postoperatively housed in an enriched environment than in rats housed in standard laboratory cages. In a comparison among different kinds of activities, social interaction was superior to wheel running, and an enriched environment allowing free physical activity combined with social interaction resulted in the best performance. We have also shown that enriched housing can improve outcome after neural grafting to a neocortical infarct. I will discuss some studies on potential mechanisms behind the environmental stimulation of outcome after focal brain ischemia.

In the studies quoted below, cortical infarct was induced by ligation of the middle cerebral artery (MCA) distal to the striatal branches in 3- to 4-month-old male spontaneously hypertensive rats. Before the operation all rats were housed in standard cages, four rats in each cage. During the first 24 to 30 postoperative hours they were housed in individual cages, then either returned to standard cages or transferred to larger cages, furnished with horizontal and inclined boards and equipped with various items. Twice or three times a week the space between the boards was changed and some objects were replaced with new ones.

Introduction

This chapter deals with blood-brain barrier dysfunction in acute and chronic hypertension and its role in the development of edematous brain lesions such as white matter changes, glial hypertrophy and morphological brain damage. The clinical relevance of experimental data is also discussed.

Acute hypertension

Blood–brain barrier (BBB) dysfunction can be observed after an acute increase in blood pressure induced by various vasoactive drugs (Johansson et al., 1970, Johansson, 1989) or by compression of the aorta (Johansson and Linder, 1974, Sokrab et al., 1988). There is no fixed level at which this occurs. Factors such as vascular tone, abruptness of the pressure increase and the drugs used all play a role. An increase in systolic pressure exceeding 60 mmHg will result in multifocal opening of the BBB to albumin in most experimental models. A number of studies have shown that the BBB dysfunction is related to vascular distension (Johansson, 1989, Table 46.1) rather than to extensive vasoconstriction – vasospasm – as earlier suggested (Byrom, 1954).

The tension in the vessel wall increases with the pressure and with the diameter of the vessels. Thus, vessels dilated by drugs or hypercapnia will be exposed to a higher stress than constricted vessels and will accordingly be more vulnerable to an increase in blood pressure (Fig. 46.1; Johansson, 1974b; 1989).