Adult dentate neurogenesis is important for certain types of hippocampal-dependent learning and also appears to be important for the maintenance of normal mood and the behavioural effects of antidepressants. Neuropeptide Y (NPY), a peptide neurotransmitter released by interneurons in the dentate gyrus, has important effects on mood, anxiety-related behaviour and learning and memory. We report that adult NPY Y -/-1 receptor knock-out mice have significantly reduced cell proliferation and significantly fewer immature doublecortinpositive neurons in the dentate gyrus. We also show that the neuroproliferative effect of NPY is dentate specific, is Y 1 -receptor mediated and involves extracellular signal-regulated kinase (ERK)1/2 activation. NPY did not exhibit any effect on cell survival in vitro but constitutive loss of the Y 1 receptor in vivo resulted in greater survival of newly generated neurons and an unchanged total number of dentate granule cells. These results show that NPY stimulates neuronal precursor proliferation in the dentate gyrus and suggest that NPYreleasing interneurons may modulate dentate neurogenesis.

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Previous studies have suggested that an increased production of the pro-inflammatory cytokines interleukin-6 (IL-6) and interleukin-1beta (IL-1beta) can influence patient outcome following a severe head injury. However, these studies have relied upon measurements of cytokine levels in CSF or serum, rather than the brain parenchyma itself. Recently, a method of intracranial microdialysis has been developed which permits the efficient recovery of macromolecules from the parenchyma. We have used this technique to investigate whether there is a correlation between patient outcome and parenchymally derived cytokines. Fourteen patients who were admitted to the Wessex Neurological Centre with severe head injury were selected for the study. This group of patients consisted of seven males and seven females with an age range of 21-77 years. Patients were treated according to standard protocols including emergency craniotomy where necessary. Microdialysis probes were implanted into the frontal region contralateral to the site of the primary injury. Approximately 200 micro l of dialysate was recovered every 8-12 h, and the concentrations of IL-6, IL-1beta and nerve growth factor (NGF) were determined by commercial enzyme-linked immunosorbent assays. Patients were assessed initially using the Glasgow coma score, and survivors were assessed after 6 months using the Glasgow outcome scale. Significantly (P = 0.04) higher levels of IL-6 were found in patients who survived compared with those who died. Also, there was a significant correlation between peak IL-6 levels and Glasgow outcome scores (r(2) = 0.34, P = 0.03, n = 14). The levels of IL-1beta and NGF were similar in both groups of patients. From these data, we suggest that IL-6 is an endogenous neuroprotective cytokine produced in response to severe head trauma.

Abstract:The relative roles of the superoxide and hydroxyl rad icals in oxidative stress-induced neuronal damage were investigated using organotypic hippocampal slice cultures. Cultures exposed to 100 ftM duroquinone, a superoxide-generating compound, for 3 h developed CAl -selective lesions over a period of 24 h. The damage accounted for '-64% of the CAl subfield, whereas CA3 showed just 6% damage, a pattern of damage comparable to that observed following hypoxia!ischaemia. Duroquinone-induced damage was attenuated by a spin-trap agent. In contrast, hydroxyl radical-mediated damage, generated by exposure to 30 jiM ferrous sulphate for 1 h, resulted in a CA3-dominant lesion. The damage developed over 24 h, similar to that observed with duroquinone, but with -45% damage in CA3 compared with only 7% in CAl. These data demonstrate a selective vulnerability of the CAl pyramidal neurones to superoxide-induced damage and suggest that of the free radicals generated following hypoxia/ischaemia, superoxide, rather than hydroxyl radical, is instrumental in producing neuronal damage.