Depression of Synaptic Transmission by Vascular Endothelial Growth Factor in Adult Rat Hippocampus and Evidence for Increased Efficacy after Chronic Seizures

Abstract

In addition to its potent effects on vasculature, it has become clear that vascular endothelial growth factor (VEGF) has effects on both neurons and glia, and recent studies suggest that it can be neuroprotective. To determine potential mechanisms underlying this neuroprotection, recombinant human VEGF was bath applied to adult rat hippocampal slices, and both extracellular and intracellular recordings were used to examine intrinsic properties and synaptic responses of hippocampal principal neurons. Initial studies in area CA1 showed that VEGF significantly reduced the amplitude of responses elicited by Schaffer collateral stimulation, without influencing membrane properties. Similar effects occurred in CA3 pyramidal cells and dentate gyrus granule cells when their major glutamatergic afferents were stimulated. Because VEGF expression is increased after seizures, effects of VEGF were also examined in rats with recurrent spontaneous seizures. VEGF reduced spontaneous discharges in slices from these rats but had surprisingly little effect on epileptiform discharges produced by disinhibition of slices from control rats. These results demonstrate a previously unknown effect of VEGF on neuronal activity and also demonstrate a remarkable potency in the epileptic brain. Based on this, we suggest that VEGF or VEGF-related targets could provide useful endpoints to direct novel therapeutic strategies for epilepsy.

Modulation of vascular endothelial growth factor (VEGF) expression in motor neurons and its electrophysiological effects

“…The ability of VEGF to suppress depolarizing inputs to brainstem motor neurons is consistent with the ability of VEGF to suppress excitatory input to pyramidal and granule neurons in the hippocampus [11].…”

“…In hippocampus, a glial mechanism was suggested to explain the effects of VEGF on synaptic transmission, because similar changes were observed on glutamatergic and GABAergic transmission, without changes in intrinsic properties [11]. In addition, the primary pattern of expression of VEGF in hippocampus appears to be punctate immunoreactivity outlining glia [6].…”

“…VEGF upregulation could be analogous to heat shock protein expression, which occurs in neurons that are exposed to insults but do not die. Given that VEGF protects neurons from insults such as experimental ischemia or seizure-induced damage [6,11,29], and motorneurons [10,25,31], it is possible that the upregulation of VEGF is an endogenous protective mechanism.…”

Effects of Salvia miltiorrhiza on CNS Neuronal Injury and Degeneration: A Plausible Complementary Role of Tanshinones and Depsides

“…Together with the evidence that VEGF expression increases after ischemia, traumatic brain injury, and seizures, it is possible that VEGF is an endogenous neuroprotective agent in the CNS. However, despite the potential importance of VEGF as a neuroprotective growth factor, few direct studies of VEGF on neurons or glia have been published to clarify its actions [67]. Astonishing, VEGF also demonstrated a remarkable potency in the epileptic brain, as a consequence, VEGF or VEGF-related targets could provide useful endpoints to direct novel therapeutic strategies for epilepsy [67].…”

“…However, despite the potential importance of VEGF as a neuroprotective growth factor, few direct studies of VEGF on neurons or glia have been published to clarify its actions [67]. Astonishing, VEGF also demonstrated a remarkable potency in the epileptic brain, as a consequence, VEGF or VEGF-related targets could provide useful endpoints to direct novel therapeutic strategies for epilepsy [67]. Finally, tanshinones are inhibitors of AChE, suggesting possible important rules in Parkinsonʼs disease but also beneficial advances in pharmacotherapy of disorders such as schizophrenia and AD [68].…”