Vascular endothelial growth factor (VEGF) is currently considered a potential pharmacologic agent for stroke therapy because of its strong neuroprotective and angiogenic capacities. Nonetheless, it is unclear how neuroprotection and angiogenesis by exogenous VEGF are related and whether they are concurrent events. In this study, the authors evaluated by stereology the effect of VEGF on neuronal and vascular volume densities of normal and ischemic brain cortices of adult male Sprague-Dawley rats. Ischemia was induced by a 4-hour occlusion of the middle cerebral artery. Low, intermediate, and high doses of VEGF165 were infused through the internal carotid artery for 7 days by an indwelling osmotic pump. The low and intermediate doses, which did not induce angiogenesis, significantly promoted neuroprotection of ischemic brains and did not damage neurons of normal brains. In contrast, the high dose that induced angiogenesis showed no neuroprotection of ischemic brains and damaged neurons of normal brains. These findings suggest that in vivo neuroprotection of ischemic brains by exogenous VEGF does not necessarily occur simultaneously with angiogenesis. Instead, neuroprotection may be greatly compromised by doses of VEGF capable of inducing angiogenesis. Stroke intervention efforts attempting to induce neuroprotection and angiogenesis concurrently through VEGF monotherapy should be approached with caution.
In the present study the "interstitial" cells of the superficial pineal gland and the nonparenchymal cells of the pineal stalk in Sprague-Dawley rats were examined ultrastructurally with the aim of defining the cells more closely. The "interstitial" cells of the superficial pineal gland do not represent a homogeneous cell population. The most abundant cell type is the mononuclear phagocyte, most easily recognized by its dark appearance and its content of primary and conspicuous secondary lysosomes. Astrocytes can be distinguished by the typical appearance of their nuclei (i.e., a thin continuous rim of heterochromatin adjacent to the nuclear membrane), identical to that of astrocytes in the CNS. Depending on the absence or presence of glial filaments and their amount, a spectrum of astrocytic cells is present. Mature astrocytes with filaments throughout their cytoplasm are rare. Immature glial cells with few or no filaments predominate. In the vicinity of blood vessels pericytes are present. In view of the fact that the "interstitial" cells could generally be identified it is suggested to abandon the term interstitial for the cells in question. In the pineal stalk mature astrocytes predominate; they have some features in common with pinealocytes, i.e., the presence of intergrade endoplasmic reticulum and grumose bodies (lysosomes). Other unusual features are a relative abundance of coated pits and vesicles. Oligodendrocytes are restricted to the proximal part of the stalk, near the deep pineal, where myelinated axons are abundant. More distally a few Schwann cells were seen.
In view of the increasing interest in the central innervation of the mammalian pineal gland, this aspect was studied in depth in the rat. This species is especially suited since the nerve fibers in question form a distinct bundle running from the deep to the superficial pineal gland through the pineal stalk. The axons were counted and analysed ultrastructurally in the pineal stalks cut transversely at three levels (proximal, intermediate, and distal) relative to the neural axis and in longitudinal sections. The number of nerve fibers was highly variable, ranging from 551 to 1,132 proximally and from 110 to 448 distally, indicating that many fibers terminate in the stalk or leave the stalk after forming a loop. Large myelinated axons, which are abundant proximally, appear to lose their sheaths along their course through the stalk. Most of the axons were small and unmyelinated. A few of these had the appearance of sympathetic fibers and disappeared after sympathectomy. Others contained abundant neurosecretory granules, and, according to the literature, may originate in the hypothalamic paraventricular nuclei. The majority of the small axons which are apparently devoid of granules and dense-cored vesicles may come from the habenular nuclei and the stria medullaris. In addition to axons, the stalk contains astrocytes, a few oligodendrocytes and Schwann cells, as well as pinealocytes identical to those of the superficial pineal gland.
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