The aim of this review is to summarize the present state of findings on altered neurotrophic factor levels in schizophrenic psychoses, on variations in genes coding for neurotrophic factors, and on the effect of antipsychotic drugs on the expression level of neurotrophic factors. This is a conceptual paper that aims to establish the link between the neuromaldevelopment theory of schizophrenia and neurotrophic factors. An extensive literature review has been done using the Pub Med database, a service of the National Library of Medicine, which includes over 14 million citations for biomedical articles back to the 1950s. The majority of studies discussed in this review support the notion of alterations of neurotrophic factors at the protein and gene level, respectively, and support the hypothesis that these alterations could, at least partially, explain some of the morphological, cytoarchitectural and neurobiochemical abnormalities found in the brain of schizophrenic patients. However, the results are not always conclusive and the clinical significance of these alterations is not fully understood. It is, thus, important to further neurotrophic factor research in order to better understand the etiopathogenesis of schizophrenic psychoses and, thus, potentially develop new treatment strategies urgently needed for patients suffering from these devastating disorders.

Nerve growth factor (NGF) is a prototype member of the neurotrophins family and has important functions in the maintenance of viability and proliferation of neuronal and non-neuronal cells, such as certain ovarian cells. The present review highlights the role of NGF and its receptors on ovarian follicle development. NGF initiates its multiple actions through binding to two classes of receptors: the high affinity receptor tyrosine kinase A (TrkA) and the low-affinity receptor p75. Different intracytoplasmic signalling pathways may be activated through binding to NGF due to variation in the receptors. The TrkA receptor activates predominantly phosphatidylinositol-3-kinase (PI3K) and mitogenic activated protein kinase (MAPK) to promote cell survival and proliferation. The activation of the phospholipase type Cγ (PLCγ) pathway, which results in the production of diacylglycerol (DAG) and inositol triphosphate (IP3), culminates in the release of calcium from the intracytoplasmic cellular stocks. However, the details of activation through p75 receptor are less well known. Expression of NGF and its receptors is localized in ovarian cells (oocyte, granulosa, theca and interstitial cells) from several species, which suggests that NGF and its receptors may regulate some ovarian functions such as follicular survival or development. Thus, the use of NGF in culture medium for ovarian follicles may be of critical importance for researchers who want to promote follicular development in vitro in the future.

Classic ideas on mechanisms for axon sprouting and nerve regeneration from peripheral nerves suggest that there is a prominent role for neurotrophin support. There has been comparatively less attention towards features of the regenerative process that develop from the proximal nerve trunk without the support of target tissues or the denervated trunk of a peripheral nerve. We studied early (2–14 d) expression of local growth factors in proximal nerve stump tips of transected sciatic nerves in rats. Immunohistochemical labelling was used to address specific deposition of BDNF, NGF, NT-3, bFGF, CNTF and IGF-1. We observed a unique localisation of BDNF, and to a much lesser extent, NGF in mast cells of injured nerve trunks but they were also observed in intact uninjured nerves. Macrophages did not express either BDNF or NGF. CNTF and IGF-1 were expressed in Schwann cells of intact nerves and stumps. We did not observe bFGF or NT-3 expression in any of the samples we studied. Mast cells may represent an important reservoir of BDNF in peripheral nerves.

Neurotrophins are a family of proteins with pleiotropic effects mediated by two distinct receptor types, namely the Trk family, and the common neurotrophin receptor p75NTR. Binding of four mammalian neurotrophins, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5), to p75NTR is studied by molecular modeling based on X-ray structures of the neurotrophins and the extracellular domain of p55TNFR, a homologue of p75NTR. The model of neurotrophin/receptor interactions suggests that the receptor binding domains of neurotrophins (loops I and IV) are geometrically and electrostatically complementary to a putative binding site of p75NTR, formed by the second and part of the third cysteine-rich domains. Geometric match of neurotrophin/receptor binding domains in the complexes, as characterized by shape complementarity statistic Sc, is comparable to known protein/protein complexes. All charged residues within the loops I and IV of the neurotrophins, previously determined as being critical for p75NTR binding, directly participate in receptor binding in the framework of the model. Principal residues of the binding site of p75NTR include Asp47, Lys56, Asp75, Asp76, Asp88, and Glu89. The additional involvement of Arg80 and Glu53 is specific for NGF and BDNF, respectively, and Glu73 participates in binding with NT-3 and NT-4/5. Neurotrophins are likely to induce similar, but not identical, conformational changes within the p75NTR binding site.