Extracellular ATP has recently been identified as an important regulator of cell death in response to pathological insults. When SN4741 cells, which are dopaminergic neurons derived from the substantia nigra of transgenic mouse embryos, are exposed to ATP, cell death occurs. This cell death is associated with prominent cell swelling, loss of ER integrity, the formation of many large cytoplasmic vacuoles, and subsequent cytolysis and DNA release. In addition, the cleavage of caspase-3, a hallmark of apoptosis, is induced by ATP treatment. However, caspase inhibitors do not overcome ATP-induced cell death, indicating that both necrosis and apoptosis are associated with ATP-induced cell death and suggesting that a necrotic event might override the apoptotic process. In this study we also found that P2X 7 receptors (P2X 7 Rs) are abundantly expressed in SN4741 cells, and both ATP-induced swelling and cell death are reversed by pretreatment with the P2X 7 Rs antagonist, KN62, or by knock-down of P2X 7 Rs with small interfering RNAs. Therefore, extracellular ATP release from injured tissues may act as an accelerating factor in necrotic SN4741 dopaminergic cell death via P2X 7 Rs. Parkinson disease (PD)2 is an idiopathic neurodegenerative disorder characterized by selective cell death of dopaminergic neurons in the substantia nigra (1). The symptoms of PD only become apparent when more than 50% of the dopaminergic neurons in the substantia nigra pars compacta are lost, which leads to an over 80% reduction in dopamine levels in the striatum (2). Epidemiological studies and pathological analyses demonstrate that sporadic PD with late onset occurs in 95% of patients, whereas the remaining 5% of PD cases are familial diseases with early onset (1, 2). Although the etiological causes of PD have not been fully elucidated, several factors have been suggested as causes of neuronal degeneration. These include environmental toxins, genetic factors, and mitochondrial dysfunction as well as proteasomal impairment and oxidative stress (3). Recently, however, there has been increasing recognition of the possible role of neuro-inflammation as a major factor in the pathogenesis of PD (4). The inflammatory component is an attractive target for therapeutic intervention. It is now generally accepted that high levels of extracellular ATP may be released under pathological conditions such as inflammation, trauma, and stress. The role of extracellular ATP and purinergic receptors in neurodegeneration is one of the focus areas of cell death research (5).P2X 7 receptors (P2X 7 Rs) are unusual purinergic receptors in that they can exist in two functional states: either as cationselective channels or as nonselective pores (6). The permeability transition of P2X 7 Rs from channel to pore occurs either upon sustained stimulation with high ATP concentrations or repeated pulses of ATP application (7). Seven members of the P2X receptor family have been cloned that share the same predicted structure with two transmembrane-spanning domains. These are a...

ObjectiveThis study was conducted to examine the following: whether patients with mild cognitive impairment (MCI) show impairments in instrumental activities of daily living (IADL) as compared to controls; to identify the functional sub-domains of instrumental activities of daily living (IADL) that are affected in MCI and, finally, to identify the Seoul-Instrumental Activities of Daily Living (S-IADL) scale cut-off score that best differentiated between MCI and controls.MethodsThis study was carried out at the geropsychiatry clinic, university hospital. The study participants included 66 patients with MCI and 61 normal elderly. The S-IADL and Seoul-Activities of Daily Living (S-ADL) scales were administered to the main caregivers of all participants in order to assess everyday functioning.ResultsThe total S-IADL score was significantly higher in the patients with MCI [mean (SD) score=4.47 (2.06)] than in the controls [mean (SD) score=1.44 (1.65)] (p<0.001). The patients with MCI performed significantly worse on IADLs, such as the ability to use the telephone, prepare meals, take medication, manage belongings, keep appointments, talk about recent events, and perform leisure activities/hobbies (p<0.05). The S-IADL scale discriminated well between patients with MCI and controls (Area Under Curve=87%).ConclusionThe patients with MCI showed impairments in the ability to perform complex ADL in comparison to healthy controls. IADLs related to memory and frontal/executive functioning were particularly affected in MCI.

Excitotoxicity and oxidative stress mediate neuronal death after hypoxic-ischemic brain injury. We examined the possibility that targeting both N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity and oxidative stress would result in enhanced neuroprotection against hypoxicischemia. 2-Hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid (Neu2000) was derived from aspirin and sulfasalazine to prevent both NMDA neurotoxicity and oxidative stress. In cortical cell cultures, Neu2000 was shown to be an uncompetitive NMDA receptor antagonist and completely blocked free radical toxicity at doses as low as 0.3 lmol/L. Neu2000 showed marked neuroprotection in a masked fashion using histology and behavioral testing in two rodent models of focal cerebral ischemia without causing neurotoxic side effects. Neu2000 protected against the effects of middle cerebral artery occlusion, even when delivered 8 h after reperfusion. Single bolus administration of the drug prevented gray and white matter degeneration and spared neurologic function for over 28 days after MACO. Neu2000 may be a novel therapy for combating both NMDA receptor-mediated excitotoxicity and oxidative stress, the two major routes of neuronal death in ischemia, offering profound neuroprotection and an extended therapeutic window.

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