Source specificity of early calcium neurotoxicity in cultured embryonic spinal neurons.

نویسندگان

  • M Tymianski
  • M P Charlton
  • P L Carlen
  • C H Tator
چکیده

To examine the role of Ca2+ in early neuronal death, we studied the impact of free intracellular calcium concentration ([Ca2+]i) on survivability in populations of cultured mouse spinal neurons. We asked whether early neurotoxicity was triggered by Ca2+ influx, whether elevated [Ca2+]i was a predictive indicator of impending neuronal death, and whether factors other than [Ca2+]i increases influenced Ca2+ neurotoxicity. We found that when neurons were lethally challenged with excitatory amino acids or high K+, they experienced a biphasic [Ca2+]i increase characterized by a primary [Ca2+]i transient that decayed within minutes, followed by a secondary, sustained, and irreversible [Ca2+]i rise that indicated imminent cell death. We showed that in the case of glutamate-triggered neurotoxicity, processes triggering eventual cell death required Ca2+ influx, and that neurotoxicity was a function of the transmembrane Ca2+ gradient. Fura-2 Ca2+ imaging revealed a "ceiling" on measurable changes in [Ca2+]i that contributed to the difficulty in relating [Ca2+]i to neurotoxicity. We found, by evoking Ca2+ influx into neurons through different pathways, that the chief determinants of Ca2+ neurotoxicity were the Ca2+ source and the duration of the Ca2+ challenge. When Ca2+ source and challenge duration were taken into account, a statistically significant relationship between measured [Ca2+]i and cell death was uncovered, although the likelihood of neuronal death depended much more on Ca2+ source than on the magnitude of the measured [Ca2+]i increase. Thus, neurotoxicity evoked by glutamate far exceeded that evoked by membrane depolarization with high K+ when [Ca2+]i was made to increase equally in both groups. The neurotoxicity of glutamate was triggered primarily by Ca2+ influx through NMDA receptor channels, and exceeded that triggered by non-NMDA receptors and Ca2+ channels when [Ca2+]i was made to rise equally through these separate pathways. The greater neurotoxicity triggered by NMDA receptors was related to some attribute other than an ability to trigger greater [Ca2+]i increases as compared with other Ca2+ sources. We hypothesize that this represents a physical colocalization of NMDA receptors with Ca(2+)-dependent rate-limiting processes that trigger early neuronal degeneration.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Role of a voltage-sensitive calcium channel blocker on inhibition of apoptosis in sensory neurons of cultured dorsal root ganglia in adult rat

Introduction: Under pathological conditions, abnormal increase in intracellular calcium concentrations is believed to induce cell death. In the present study, a voltage-sensitive calcium channel blocker (loperamide hydrochloride) was used to investigate its role in inhibition of apoptosis in sensory neurons of cultured spinal dorsal root ganglia (DRG). Methods: L5 DRG from adult rats were di...

متن کامل

Cholinergic Differentiation of neural precursor cells derived from mouse embryonic stem cells increased by Shh, LIF and RA

Introduction Cholinergic system is one of the important systems of mammalian CNS. Cholinergic neurons distributed in brain and spinal cord and contributed to principal functions like: consciousness, learning and memory, and motor control. In this study we investigated the differentiation potentiality of mouse embryonic stem cells toward cholinergic neurons. The aim of this study was to evaluate...

متن کامل

C-terminal fragments of APP: Its neurotoxic mechanisms and involvement in gene transcription

Several lines of evidence suggest that some neurotoxicity in AD is due to proteolytic fragments of APP. In this study, we compared the potency of neurotoxicity induced by CT with that of A-beta neurotoxicity and our results showed that various CT peptide fragments (CTFs; CTF99, AICD, CTF31) caused neurotoxicity in cultured cells and primary cortical neurons, induced strong non-selective inward ...

متن کامل

C-terminal fragments of APP: Its neurotoxic mechanisms and involvement in gene transcription

Several lines of evidence suggest that some neurotoxicity in AD is due to proteolytic fragments of APP. In this study, we compared the potency of neurotoxicity induced by CT with that of A-beta neurotoxicity and our results showed that various CT peptide fragments (CTFs; CTF99, AICD, CTF31) caused neurotoxicity in cultured cells and primary cortical neurons, induced strong non-selective inward ...

متن کامل

Protective effect of curcumin and Curcuma longa extract on apoptosis of motor neurons in cultured spinal cord slices of adult mouse

Introduction: Since Curcuma longa extract and curcumin have been shown to be potent antioxidant agents, they were used in cultured adult mouse spinal cord slices to investigate whether they can inhibit apoptosis in motor neurons. Methods: Slices from the thoracic region of adult mice spinal cord were divided into four groups: 1. Freshlyprepared slices (time 0) 2. Control 3. Slices treated by cu...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • The Journal of neuroscience : the official journal of the Society for Neuroscience

دوره 13 5  شماره 

صفحات  -

تاریخ انتشار 1993