A decline in cognitive ability is a typical feature of the normal aging process, and of neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's diseases. Although their etiologies differ, all of these disorders involve local activation of innate immune pathways and associated inflammatory cytokines. However, clinical trials of anti-inflammatory agents in neurodegenerative disorders have been disappointing, and it is therefore necessary to better understand the complex roles of the inflammatory process in neurological dysfunction. The dietary phytochemical curcumin can exert anti-inflammatory, antioxidant and neuroprotective actions. Here we provide evidence that curcumin ameliorates cognitive deficits associated with activation of the innate immune response by mechanisms requiring functional tumor necrosis factor α receptor 2 (TNFR2) signaling. In vivo, the ability of curcumin to counteract hippocampus-dependent spatial memory deficits, to stimulate neuroprotective mechanisms such as upregulation of BDNF, to decrease glutaminase levels, and to modulate N-methyl-D-aspartate receptor levels was absent in mice lacking functional TNFRs. Curcumin treatment protected cultured neurons against glutamate-induced excitotoxicity by a mechanism requiring TNFR2 activation. Our results suggest the possibility that therapeutic approaches against cognitive decline designed to selectively enhance TNFR2 signaling are likely to be more beneficial than the use of anti-inflammatory drugs per se.

/pdf/curcumin-requires-tumor-necrosis-factor-a-signaling-to-503zpd8eod.pdf

Curcumin requires tumor necrosis factor α signaling to alleviate cognitive impairment elicited by lipopolysaccharide.

Glutamate neurotoxicity and diseases of the nervous system

Calcium-mediated neurotoxicity: relationship to specific channel types and role in ischemic damage.

It has been commonly assumed that calcium, which normally serves important functions as a membrane stabilizer, metabolic regulator, and sec­ ond messenger, also can mediate anoxic and toxic cell death (Schanne et aI., 1979; Farber, 1981; Trump et aI., 1981). It is then postulated that when the plasma membrane becomes unduly permeable to calcium, the free cytosolic concentration (Ca2+) rises to toxic levels. As applied to the brain, this hypothesis predicts that loss of cellular calcium ho­ meostasis underlies selective neuronal vulnerability in ischemia, hypoglycemia, and epileptic seizures (Siesj6, 1981; Meldrum, 1983; Raichle, 1983; for further literature, see Siesj6 and Wieloch, 1985; Siesj6, 1988). It should be clearly understood that ischemia, particularly if dense, causes all cells to loose their calcium homeostasis. The hypothesis predicts, therefore, that some cells are more vulner­ able than others because they have a higher density of calcium channels in their plasma membranes. Presumably, this could lead to untolerable local in­ creases in calcium concentration. In a recent extension of the calcium hypothesis, it was speculated that increased calcium cycling across ischemia-damaged membranes leads to a sustained rise in Ca2 + j and slow calcium overload of mitochondria, thereby causing delayed neuronal death (Deshpande et aI., 1987; see also Martins et aI., 1988). Dux et aI. (1987), inducing transient isch­ emia in the gerbil, recently assessed the time course of mitochondrial calcium deposits in glia cells and in pyramidal cells of the hippocampus CAl sector and

https://journals.sagepub.com/doi/pdf/10.1038/jcbfm.1989.20

Calcium fluxes, calcium antagonists, and calcium-related pathology in brain ischemia, hypoglycemia, and spreading depression: a unifying hypothesis.

Glutamate excitotoxicity is a hypothesis that states excessive glutamate causes neuronal dysfunction and degeneration. As glutamate is a major excitatory neurotransmitter in the central nervous system (CNS), the implications of glutamate excitotoxicity are many and far-reaching. Acute CNS insults such as ischaemia and traumatic brain injury have traditionally been the focus of excitotoxicity research. However, glutamate excitotoxicity has also been linked to chronic neurodegenerative disorders such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson’s disease and others. Despite the continued research into the mechanisms of excitotoxicity, there are currently no pharmacological interventions capable of providing significant neuroprotection in the clinical setting of brain ischaemia or injury. This review addresses the current state of excitotoxic research, focusing on the structure and physiology of glutamate receptors; molecular mechanisms underlying excitotoxic cell death pathways and their interactions with each other; the evidence for glutamate excitotoxicity in acute neurologic diseases; laboratory and clinical attempts at modulating excitotoxicity; and emerging targets for excitotoxicity research.

Glutamate receptors, neurotoxicity and neurodegeneration

The effects of the glutamate N-methyl-D aspartate (NMDA) receptor antagonist, MK-801, upon ischemic brain damage has been examined in anesthetized cats. Focal cerebral ischemia was produced by permanent occlusion of one middle cerebral artery and the animals were killed 6 h later. The amount of early ischemic damage was assessed in coronal sections at 16 predetermined stereotactic planes. Pretreatment with MK-801 (5 mg/kg, i.v.), 30 min before occlusion of the middle cerebral artery significantly reduced the volume of ischemic damage (from 32.7 ± 4.0% of the cerebral hemisphere in vehicle-treated cats to 16.2 ± 4.5% in MK-801-treated cats). NMDA receptor antagonists that penetrate the blood-brain barrier, such as MK-801, merit further study as protective agents against ischemic brain damage.

https://journals.sagepub.com/doi/pdf/10.1038/jcbfm.1988.18

Protective effect of the glutamate antagonist, MK-801 in focal cerebral ischemia in the cat.

Excessive activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor has been implicated in the sequence of neurochemical events in cerebral ischaemia that results in irreversible neuronal damage. The effects of the NMDA antagonist MK 801 upon the amount of ischaemic brain damage has been assessed quantitatively in a cat and in a rat model of focal cerebral ischaemia.

Glutamate receptor antagonists in experimental focal cerebral ischaemia.

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Protective effect of the glutamate antagonist, MK-801 in focal cerebral ischemia in the cat.

Glutamate receptor antagonists in experimental focal cerebral ischaemia.