In many neurologic disorders, injury to neurons may be caused at least in part by overstimulation of receptors for excitatory amino acids, including glutamate and aspartate. These neurologic conditions range from acute insults such as stroke, hypoglycemia, trauma, and epilepsy (Table 1) to chronic neurodegenerative states such as Huntington's disease, the acquired immunodeficiency syndrome (AIDS) dementia complex, amyotrophic lateral sclerosis, and perhaps Alzheimer's disease (Table 2)1–3. Glutamate is the principal excitatory neurotransmitter in the brain, and its interactions with specific membrane receptors are responsible for many neurologic functions, including cognition, memory, movement, and sensation4. In addition, excitatory . . .

Excitatory amino acids as a final common pathway for neurologic disorders.

Chronic ethanol consumption:from neuroadaptation to neurodegeneration

Although thrombolysis with tissue plasminogen activator (tPA) is a stroke therapy approved by the US Food and Drug Administration, its efficacy may be limited by neurotoxic side effects1,2. Recently, proteolytic damage involving matrix metalloproteinases (MMPs) have been implicated. In experimental embolic stroke models, MMP inhibitors decreased cerebral hemorrhage and injury after treatment with tPA3,4. MMPs comprise a family of zinc endopeptidases that can modify several components of the extracellular matrix5,6. In particular, the gelatinases MMP-2 and MMP-9 can degrade neurovascular matrix integrity. MMP-9 promotes neuronal death by disrupting cell-matrix interactions7, and MMP-9 knockout mice have reduced blood-brain barrier leakage and infarction after cerebral ischemia8. Hence it is possible that tPA upregulates MMPs in the brain, and that subsequent matrix degradation causes brain injury. Here we show that tPA upregulates MMP-9 in cell culture and in vivo. MMP-9 levels were lower in tPA knockouts compared with wild-type mice after focal cerebral ischemia. In human cerebral microvascular endothelial cells, MMP-9 was upregulated when recombinant tPA was added. RNA interference (RNAi) suggested that this response was mediated by the low-density lipoprotein receptor–related protein (LRP), which avidly binds tPA9 and possesses signaling properties10. Targeting the tPA-LRP signaling pathway in brain may offer new approaches for decreasing neurotoxicity and improving stroke therapy.

Lipoprotein receptor-mediated induction of matrix metalloproteinase by tissue plasminogen activator.

With the increasing use of mobile communication, concerns have been expressed about the possible interactions of electromagnetic radiation with the human organism and, in particular, the brain. The effects on neuronal electrical activity, energy metabolism, genomic responses, neurotransmitter balance, blood-brain barrier permeability, cognitive function, sleep, and various brain diseases including brain tumors are reviewed. Most of the reported effects are small as long as the radiation intensity remains in the nonthermal range, and none of the research reviewed gives an indication of the mechanisms involved at this range. However, health risks may evolve from indirect consequences of mobile telephony, such as the sharply increased incidence rate of traffic accidents caused by telephony during driving, and possibly also by stress reactions which annoyed bystanders may experience when cellular phones are used in public places. These indirect health effects presumably outweigh the direct biological perturbations and should be investigated in more detail in the future.

Effects of electromagnetic radiation of mobile phones on the central nervous system

Tumor necrosis factor α (TNFα) is widely expressed in both neurons and glia and has been shown to be upregulated after traumatic brain injury (TBI). TNFα receptor activation results in activation of the transcription factor nuclear factor κB (NF-κB), which may serve an antiapoptotic role via the induction of target genes manganese superoxide dismutase (MnSOD) and/or calbindin. In the present study, we used a controlled cortical impact model of TBI with pertinent lines of transgenic mice to combine both morphological characterization and molecular analysis to elucidate the role of TNFα after TBI. Measurements of both the lesion volume and the blood–brain barrier breach indicated exacerbations in mice rendered genetically deficient in both the p55 and p75 TNFα receptors (TNFR-KO) compared with wild-type animals. Additionally, animals genetically altered to overexpress MnSOD showed a significant decrease in lesion volume compared with that of control littermates, whereas no alterations were observed in mice lacking the calcium-binding protein calbindin D28k. Analysis of NF-κB activation and relative levels of MnSOD revealed delayed responses in the injured cortex of TNFR-KO animals compared with wild-type animals, implying that endogenous TNFα may be neuroprotective after TBI.

https://www.jneurosci.org/content/jneuro/19/15/6248.full.pdf

Exacerbation of Damage and Altered NF-κB Activation in Mice Lacking Tumor Necrosis Factor Receptors after Traumatic Brain Injury

Capillary NMDA receptors regulate blood-brain barrier function and breakdown.

We recently presented evidence that the reversible opening of the blood-brain barrier (BBB) by the infusion of 1.6 M mannitol into the rat internal carotid artery is mediated by a rapid stimulation of ornithine decarboxylase (ODC) activity and putrescine synthesis in cerebral capillaries. We have now investigated this hypothesis further, using isolated rat cerebral capillaries as an in vitro model of the BBB. The ODC activity of cerebral capillary preparations was enriched up to 15-fold over that of the cerebral homogenate. Hyperosmolal mannitol in physiological buffer evoked a rapid (<15 s), concentration- and time-dependent increase in capillary ODC activity and an accumulation of putrescine and spermidine which was blocked by the specific ODC inhibitor, α- difluoromethylornithine (DFMO, 10 m M). Mannitol (1 M), as well as 2 M urea, evoked a two- to fivefold increase in the temperature-sensitive influx of 45Ca2+ and uptake of horseradish peroxidase (HRP) and 2-deoxy-D-[1-3H]glucose (DG), but not α-[1-14C]aminoisobutyrate, during a 2-min incubation. DFMO (10 mM) abolished 1 M mannitol-mediated stimulation of 45Ca2+ influx and uptake of HRP and DG, whereas 1 mM putrescine replenished capillary polyamines and reversed the DFMO effects. Mannitol (1 M)-induced stimulation of ODC activity and membrane transport processes was Ca2+-dependent and verapamil- and nisoldipine-sensitive. Phorbol myristate acetate (PMA, 10 nM), a protein kinase C activator, also evoked a two- to threefold stimulation of 45Ca2+ transport and HRP and DG uptake. This PMA effect was abolished by DFMO, suggesting involvement of rapid, ODC-controlled polyamine synthesis. The effects of 10 nM PMA and 1 M mannitol were additive, suggesting that hyperosmolal stimulation of ODC-activated polyamine synthesis does not involve protein kinase C. These data support the hypothesis that ODC-activated polyamine synthesis and Ca2+ influx (via Ca2+ channels) play a key role in mediating the effects of hyperosmolality on BBB permeability.

Polyamines and Ca2+ mediate hyperosmolal opening of the blood-brain barrier: in vitro studies in isolated rat cerebral capillaries.

We investigated the role of polyamines and their regulatory enzyme ornithine decarboxylase in N-methyl-D-aspartate-induced excitotoxicity in embryonic chick retina. N-Methyl-D-aspartate (200 microM) produced an early increase in ornithine decarboxylase activity, putrescine concentration, and Ca2+ entry, leading to selective neuronal death by 30 min. This response was attenuated by the ornithine decarboxylase inhibitor alpha-difluoromethylornithine and the N-methyl-D-aspartate receptor antagonist 5-aminophosphonovaleric acid. Exogenous putrescine increased intracellular putrescine and spermine levels and reversed neuroprotection by alpha-difluoromethylornithine, but not by 5-aminophosphonovaleric acid. N-Methyl-D-aspartate-receptor stimulation of putrescine/polyamine synthesis mediates abnormal Ca2+ entry and acute excitotoxic neuronal death. Postreceptor inhibition of the ornithine decarboxylase/polyamine cascade by alpha-difluoromethylornithine may provide neuroprotection against N-methyl-D-aspartate-induced excitotoxicity.

N-Methyl-d-Aspartate Receptor Excitotoxicity Involves Activation of Polyamine Synthesis: Protection by α-Difluoromethylornithine

Ligation-induced acute pancreatitis in rats and opossums: a comparative morphologic study of the early phase.

Four hours following cryo-injury rat cerebral pericapillary astrocytes from the perilesional area were markedly swollen occupying 17% of the pericapillary space as compared to 11% in sham operated controls. Ornithine decarboxylase activity and polyamine levels were increased over sham controls. The astrocytic swelling, the percentage of the pericapillary space occupied by astrocytic processes, and polyamine levels were reduced to near control levels by the following: (1) α-difluoromethylornithine; (2) Ifenprodil; and (3) MK-801. α-Difluoromethylornithine is a specific inhibitor of ornithine decarboxylase, Ifenprodil is an inhibitor of the polyamine binding site on the n-methyl-d-aspartate receptor, and MK-801 is an antagonist to n-methyl-d-aspartate binding to the n-methyl-d-aspartate receptor. Addition of putrescine, the product of ornithine decarboxylase activity, reversed the effect of α-difluoromethylornithine and restored the pericapillary swelling. Putrescine did not affect the MK-801-induced reduction in pericapillary astrocytic swelling. Therefore, polyamines and the n-methyl-d-aspartate receptor modulate excitotoxic responses to cryo-injury in pericapillary cerebral astrocytes.

Jerome J. Trout

Papers

Capillary NMDA receptors regulate blood-brain barrier function and breakdown.

Polyamines and Ca2+ mediate hyperosmolal opening of the blood-brain barrier: in vitro studies in isolated rat cerebral capillaries.

N-Methyl-d-Aspartate Receptor Excitotoxicity Involves Activation of Polyamine Synthesis: Protection by α-Difluoromethylornithine

Ligation-induced acute pancreatitis in rats and opossums: a comparative morphologic study of the early phase.

Polyamines and NMDA receptors modulate pericapillary astrocyte swelling following cerebral cryo-injury in the rat.