Neurotrophic factors are a family of proteins, which are involved in the regulation of cell survival and programmed neuronal cell death during development . The capacity of various neurotrophic factors to affect neurons is often developmentally regulated . Some of these factors including brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) [50, 51] were demonstrated as neuroprotective in experimental models of hypoxia-ischemia. The levels of BDNF were decreased in CA1 neurons of the hippocampus, following hypoxia-ischemia; this was followed by onset of DNA fragmentation and subsequent neuronal death. On the other hand, most of the BDNF-immunopositive neurons did not undergo apoptosis after hypoxia-ischemia . Astrocytes are known to release neurotrophic factors such as platelet-derived growth factor (PDGF), CNTF, BDNF, neurotrophins (NT)-3 and NT-4 [53, 54], all of which have been reported to support proliferation and survival of oligodendrocyte progenitor cells [55, 56]. LPS was shown to disturb the development of these cells, or even to be cytotoxic, by inducing astrocytes or microglia to produce pro-inflammatory factors such as TNF-α, IL-1β, IL-6 and nitric oxide (NO). In addition, LPS could induce cytotoxicity by suppressing the production of neurotrophic factors by astrocytes .
The process of angiogenesis drives maturation and elaboration of the primary vascular network via proliferation and migration of endothelial cells . Vascular endothelial growth factor (VEGF), is a polypeptide growth factor, which acts as an endothelial cell survival factor and a vascular permeability factor . In addition, VEGF regulate angiogenesis when acting in combination with other factors such as angiopoietin (Ang)-1 and -2 . Although several growth factors and cytokines influence the expression of VEGF, tissue hypoxia is suggested as the major stimulating factor for the upregulation of VEGF in vivo .
Endothelin-1 (ET-1) is one of the most potent vasoconstrictors known . ET-1 is a mitogenic  and anti-apoptotic factor  in many cell types including endothelial cells and astrocytes. Within the CNS, ET-1 was demonstrated in various neuronal groups [64, 65] and in glial cells under pathological conditions . Under ischemia and Alzheimer's disease, ET-like immunoreactivity has been detected in astrocytes [67, 68]. ET-1 was suggested to play a key role in the development of cerebral vasospasm . Proinflammatory cytokines such as IL-1, TNF-α and transforming growth factor-β, which are produced during endotoxemia, are also increased the production of ET-1 from endothelial cells . Thus, it is possible to suggest that ET could be one of the autocrine/paracrine factors in the different brain regions of the fetus that should be considered under intrauterine infection.
Nitric oxide (NO) plays an important role in the pathogenesis of neuronal injury during cerebral ischemia. NO is the product of enzymatic activity of the constitutive endothelial NO synthase (eNOS), neuronal (nNOS) and inducible (iNOS) isoforms of this enzyme. After ischemia, NO was associated with cerebral vasodilatation (via inducing eNOS activity), and inhibition of platelet aggregation and leukocyte adhesion (via activation of nNOS in neurons and iNOS in microglia and astrocytes) [70, 71]. During development, the expression of nNOS parallels that of the glutamate receptor and corresponds to regions of selective vulnerability to hypoxia-ischemia [70, 71]. Destruction of neurons containing nNOS in the neonatal rat prior to hypoxia-ischemia lowered the injury score and the frank infraction in the cortex [70, 71]. In addition, neonatal mice with targeted destruction of the nNOS gene were markedly protected from injury to neurons in hippocampus and cortex, when also subjected to hypoxia-ischemia insult. The influx of intracellular calcium is increased during cerebral ischemia, and results in activation of nitric oxide-synthase (NOS) and the production NO. NO, like free iron, can increase the toxicity of superoxide radicals, and thus cause neuronal cell damage [70–72].
Apoptosis in the developed brain (under normal physiological conditions) is believed to occur mostly during prenatal development, decline early post-natally and to be minimal in adult brain [71, 72]. Ischemia and many other acute and chronic neurodegenerative processes trigger apoptosis [70, 71]. Regulation of caspase-3 by BDNF was demonstrated in the neuronal cell bodies and in the striatum and hippocampus following hypoxia-ischemia . Also, upregulation of CD95 (FasL) (the cell surface receptor which induces apoptotic death) was demonstrated in the hippocampus, and thalamus following hypoxia-ischemia injury to the developing rat brain [70, 71, 74].
The neuropeptides alpha-melanocyte-stimulating hormone (α-MSH) is a proopiomelanocortin derivate that show anti-inflammatory effect within the brain. It regulates and mediates the communication between nervous, endocrine and immune system. It is produced by pituitary cells, neurons, keratinocytes and macrophages . The anti-inflammatory activity of a-MSH was demonstrated in different disease including endotoxemia/ischemia [75–77]. The anti-inflammatory activity of α-MSH include suppression of inflammatory cytokine expression such as TNF-α, interferon-γ, IL-1, IL-6 and IL-8, and also the inhibition of inflammatory activity of neutrophils and monocytes [75, 77]. It also blocked LPS-induced expression of TNF-a . In addition, α-MSH was upregulated the anti-inflammatory cytokine IL-10 . Recently, it was demonstrated that α-MSH levels were decreased in plasma of patients with acute brain injury; these levels were in a negative correlation with TNF-α levels . It was also shown that α-MSH acts directly within the brain (through microglia) to modulate local inflammation . Alpha-MSH was demonstrated to inhibit brain tumor necrosis factor-alpha (TNF-alpha), which is involved in human neurodegenerative diseases, induced by local injection of lipopolysaccharide. Ischemia/reperfusion of the brain was shown to induce inflammation in the CNS, and application of α-MSH (systemically) modulated this process. It was demonstrated that such influences of the peptide may occur through inhibition of inflammatory agents produced by glia. Alpha-MSH modulated TNF-alpha and nitric oxide produced by activated murine microglia, and TNF-alpha produced by human astrocytes. Since glial cells can secrete an d react to alpha-MSH, it is suggested that these cells act as autocrine regulatory element, which can regulate both fever and inflammation in the brain [82–84].
Thus, it is possible to suggest that α-MSH could be involved in the regulation of the inflammatory processes in the fetal brains of mothers with intrauterine infection, and to be suggested as a possible treatment of CNS disorders that have an inflammatory component.
The involvement of the above factors and mechanisms in the pathophysiology of intrauterine infection during pregnancy and offspring brain damage and development is not yet clear.