DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

ISCHEMIA
381
PL
PLA 2
Arachidonic
acid
O 2
–
DAG
PKC
COX
LOX
Lipid peroxidation
products
Destabilization
of membranes
Eicosanoids
PIP 2
PLC
G q
IP 3
mGluR
Endoplasmic
reticulum
Peroxynitrite
CELL
DEATH
Glutamate release
NMDA-R
Ca 2+
NO
synthase
NO
Glu-R
O –
2
H 2 O 2
V
S
C
C
Ca 2+
N
C
X
Na + Ca 2+ Na +
APOPTOTIC SIGNALING
mtPTP
Cytosolic cytochrome C
Caspase activity
DNA damage
Cytoskeletal damage
Impaired energy production
Figure 14–13. Mechanisms contributing to neuronal injury during ischemia-reperfusion. Several pathways contribute to excitotoxic neuronal
injury in ischemia, with excess cytosolic Ca 2+ playing a precipitating role. DAG, diacylglycerol; GluR, AMPA/kainate type of glutamate
receptors; IP 3
, inositol trisphosphate; mGluR, metabotropic glutamate receptor; NMDA-R, N—methyl-D-aspartate receptor; O 2−
,
superoxide radical; PIP 2
, phophatidyinositol 4,5-bisphosphate; PKC, protein kinase C; PL, phospholipids, PL phospholipase, VSCC,
voltage-sensitive Ca 2+ channel. COX, cyclooxygenase; LOX, lipoxygenase; NCX, NA + /Ca 2+ exchanger; mtPTP, mitochondrial permeability
transition pore. (Reproduced with permission from Dugan LL, Kim-Han JS: Hypoxic-ischemic brain injury and oxidative stress,
in Siegel GS, Albers RW, Brady S, Price D (eds): Basic Neurochemistry: Molecular, Cellular, and Medical Aspects, 7th ed. Burlington,
MA: Elsevier Academic Press, 2006, p 564. Copyright © 2006, American Society for Neurochemistry. All rights reserved.)
CHAPTER 14
NEUROTRANSMISSION AND THE CENTRAL NERVOUS SYSTEM
Glutamate Excitotoxicity. High concentrations of glutamate lead to
neuronal cell death by mechanisms that have only recently begun to
be clarified (Figure 14–13). The cascade of events leading to neuronal
death is thought to be triggered by excessive activation of NMDA or
AMPA/kinase receptors, allowing significant influx of Ca 2+ into neurons.
Glutamate- mediated excitotoxicity may underlie the damage
that occurs after ischemia or hypoglycemia in the brain, during which
a massive release and impaired reuptake of glutamate in the synapse
leads to excess stimulation of glutamate receptors and subsequent
cell death. NMDA receptor antagonists can attenuate neuronal cell
death induced by activation of these receptors (Haeberlein and Lipton,
2009). Because of their widespread distribution in the CNS, glutamate
receptors have become targets for diverse therapeutic interventions. For
example, a role for disordered glutamatergic transmission in the
etiology of chronic neurodegenerative diseases and in schizophrenia
has been postulated (Chapters 16 and 22).
Acetylcholine. Based on a non- homogeneous distribution within the
CNS and the observation that peripheral cholinergic drugs could produce
marked behavioral effects after central administration, many
investigators addressed the possibility that ACh might also be a central
neurotransmitter. In the late 1950s, Eccles and colleagues identified
ACh as a neurotransmitter for the excitation of spinal cord
Renshaw interneurons by the recurrent axon collaterals of spinal
motoneurons. Subsequently, the capacity of ACh to elicit neuronal
discharge has been replicated on scores of CNS cells (Shepherd,
2003). Eight major clusters of ACh neurons and their pathways have
been characterized (Cooper et al., 2003; Nestler et al., 2009;
Shepherd, 2003). For additional details, see Chapter 9.