The reported number of biological modulatory molecules that mediate in brain repair is high and ever-growing. Besides NGF, which has been reported to improve cholinergic function, stimulate axonal growth, cerebral perfusion and neurogenesis by stimulating proliferation through tyrosine kinase receptor signalling [16, 17], the administration of other factors, like basic fibroblast growth factor (bFGF), has been shown to promote neurogenesis in both intact and ischaemic brain . Indeed, intracysternal administration 1 day after experimental stroke in rats has been shown to stimulate progenitor cell proliferation in the subventricular zone (SVZ) and dentate gyrus (DG), important areas for the development of new neurons in the adult brain . While higher levels seem to be required after damage , it is important to emphasize that trophic factors not only act in disease but also under normal conditions to maintain tissue homeostasis. This has been reported in brain-derived neurotrophic factor (BDNF) signalling, impairment of which may cause progressive neuronal dysfunction in animal models . In this sense, intravenous administration of BDNF during the 5 days following cortical photothrombotic stroke is associated with enhanced migration of progenitor cells from the SVZ and increased neurogenesis in the DG on DCX- and NeuN-stained slices .
How can brain repair be modulated by the action of factors like BDNF? Although still unclear, white matter glial cells have been reported to play a key role in protecting and promoting the regeneration of nerve fibres by producing BDNF itself . Also, prostacyclin, an important hormone released in response to vascular damage is stimulated around cerebral arteries when this factor is present . From a genetic perspective, it is known that BDNF can activate NF-kB through the TrkB-PI3-Kinase-Akt pathway  and that this activation leads to the downstream activation of genetic programs that contribute to protecting cells from stress conditions such as serum starvation, glutamate toxicity or ischaemia , all of which occur at the beginning of the ischaemic insult.
It bears mentioning that trophic factors not only enhance single processes like neurogenesis, but they also exert pleiotropic effects on other biological pathways such as vascular function, immune cell function or cell death. In this sense, it was recently reported that the preserved neuronal loss and reduced number of TUNEL-positive cells after intranasal administration of BDNF might also be due to modulation of local inflammation by this factor, which would reduce tumour necrosis factor-α (TNF-α) levels and augment those of interleukin (IL)-10 .
However, in addition to all of this pleiotropic interplay, the activity of most of these factors within the brain under ischaemic conditions is not clear. After the hypoxic insult, many hypoxia-response genes such as HIF-1alpha are upregulated, triggering downstream changes in other interacting genes such as vascular endothelial growth factor (VEGF), which is the key gene for the angiogenesis induced in penumbral regions of the brain. This angiogenesis is known to depend on several factors including VEGF, VEGFR2, Angiopoietins 1 and 2 and its Tie2 receptors . In a recent study, inhibition of VEGF receptor 2 after ischaemia worsened injury and also affected cell death patterns with a shift from apoptosis to a necrosis phenotype . In many other studies in which VEGF was administrated following stroke, the growth factor was shown to enhance brain repair processes [29, 30]. For all these reasons VEGF and its signalling of vasculogenesis has attracted much interest in recent years, revealing that neurogenesis is not the only process that responds to trophic factor therapy among possible brain repair therapies. Indeed, some trophic factors such as insulin growth factor-1, which has been reported to promote recovery after stroke [31-33], exert their activity in different routes by enhancing endothelial function, regulating apoptosis and having anti-inflammatory properties instead of just affecting neurogenesis [34, 35].
Another process that is modulated by brain repair therapies is myelin formation. Again, we emphasize the importance of connections between elements of the different pathways involved in brain repair after ischaemia. Recent publications have suggested connections within signal transduction pathways between elements such as Lingo-1 and epidermal growth factor . Given that Lingo1 antibodies can promote recovery from demyelinating disease in animal models , trophic factors that might modulate Nogo-A or Lingo1 activities may offer interesting possibilities for brain repair. Important inhibitors of axonal remodelling, such as Nogo-A, are augmented after cerebral ischaemia  and their inhibition through viral-mediated RNAi enhances axonal connectivity ; therefore, strategies that enhance myelin formation and axonal remodelling through trophic factors are a possible way forward in stroke research.
Other possible treatment approaches are blood-mobilizing drugs like erythropoietin (EPO) [40-42] or Granulocyte colony-stimulating factor (G-CSF), which have been shown to have positive results in animal models [43, 44]. Interestingly, higher levels of neovascularization and endogenous stem cell biological activity were observed when these factors were combined in a recent study . In light of these results, an open question in trophic factor therapy is whether augmented efficacy could be obtained by applying these factors in specific combinations instead of using any one factor alone.
On the other hand, some other drugs with trophic effects, like CDP-choline, which have been attributed with a protective role [46, 47], have come under investigation. Although its mechanisms of action are unknown, it is thought that CDP-choline improves both the structural integrity and functionality of the neuronal membranes, and this may in turn assist membrane repair . Experimental animal studies have demonstrated that CDP-choline not only promotes protective mechanisms (decreasing gliosis and cell death) but also seems to stimulate repair (increasing endogenous cellular proliferation, angiogenesis and synaptogenesis) . Another drug that has been attributed with a protective role is Cerebrolysin, which has exhibited trophic properties when applied 24 and 48 hrs after stroke in animal models of ischaemia . Indeed, while infarction volume does not seem to be substantially reduced with this treatment, the functional outcome is improved and proliferation, migration and survival of neuroblasts, especially in the peri-infarct area, have been thought to contribute to the observed results [51, 52].