Excitotoxcity and neurotoxicity Flashcards
when dose excitotoxcity occur
Excitotoxicity occurs when excessively high levels of the neurotransmitter glutamate act on ionotropic and metabotropic receptors resulting in depolarisation, Ca2+ influx and thus more glutamate release
Ultimately this leads to cell death as mitochondrial function is disrupted resulting in ATP depletion and the production of reactive oxygen species
what is the process of neurotransmission
neurotransmitter molecules are packaged into membranous vesicles in presynaptic terminal. when the membrane depolarises by voltage gated calcium to open the increase in intracellular calcium triggers fusion. Transmitter is then released into extracellular space in quanta sized amounts and diffusions passively across cleft. Some bien to post and activated receptors trigger even on G protein cascade. Eventually cleared by continued diffusion, enzymatic degradation or active uptake into cells.
example of excitatory neurotransmitters
Glutamate (Glu) Acetylcholine (ACh) Histamine Dopamine (DA) Norepinephrine (NE); also known as noradrenaline (NAd) Epinephrine (Epi); also known as adrenaline (Ad)
examples of inhibitory neurotransmitters
Inhibitory neurotransmitters gamma-Aminobutyric acid (GABA) Serotonin (5-HT) Dopamine (DA)
glutamate is a major excitatory neurotransmitter but can cause excitotoxicity resulting in calcium overload. what is one line of defence against this
mitochondrial metabolism
neurones exposed to excessive glutamate show what
cell swelling
dendritic beading
ROS
ion dyshomeostasis
mitochondira distress cause ca move in and apoptosis and cell death
what cells prevent excitotoxicity
astrocytes
what ion overload increase ROS production causing mitochondrial damage
calcium
what are neuropeptides and why are they different to neurotransmitters
Neuropeptides may be a subtype of neurotransmitters
larger released more slowly ( 50ms compared to 0.1ms) last longer can act at distal sites cannot be re-uptjaane for reuse
examples of neuropeptides
vasopressin cholecystokinin endorphins somatostatin ACTH/MSH
example of neruotrasnitters
glutamate
asparate
serotonin ACH
GABA
what is long term potentiation
Long-term potentiation (LTP) is a process involving persistent strengthening of synapses that leads to a long-lasting increase in signal transmission between neurons.
organophosphate poisoning uses ACH what are the symptoms
bradycardia
SLUDGE
salivation, lacrimation, urination, diarrhea, GI upset, emesis
DUMBELS (diaphoresis and diarrhea; urination; miosis; bradycardia, bronchospasm, bronchorrhea; emesis; excess lacrimation; and salivation
benzodiazepine overdose - caused by like lorazepam uses what neurotrnamsiiter and what effects
GABA = GABAa receptor
large pupil s
respiratorydepression
agitation and cyanosis and tremors and confusion
difference between the two gaba receptors
There are two classes of GABA receptors: GABAA and GABAB. GABAA receptors are ligand-gated ion channels (also known as ionotropic receptors); whereas GABAB receptors are G protein-coupled receptors, also called metabotropic receptor
opioid overdose can causes bradypnoea and pinpoint pupils what neurotransmitter is used in this case
opiates such as endorphins
depression uses what neurotransmitter
serotonin
sleep deprivation , low self-esteem , no pleasure in activities
phenyl ketone urea PKU is an excess of the neurotransmitter phenylalanine which is a precursor for dopamine, melanin. what symptoms
musty odor seizures itnellectual disability eczema , repeatedly sick fairer skin and tantrums
neurotoxins are destructive to nervous tissue and can be endogenous or exogenous what are some examples
tetanus toxin, heavy metals such as arsenic
leads to excitotoxicity
define excitotoxicity
Over-excitation of neurons can lead to toxicity, and cell death
Usually safe chemicals (e.g. glutamate, NMDA) cause toxicity
Caused by prolonged high-levels that cause cellular damage
This is associated with a variety of diseases
in usual health glutamate bind to receptors. Calcium enters the cell from outside, and from the ER. Sodium enters the cell, allowing more Calcium to enter (via Na+/Ca2+ exchangers. This triggers depolarisation, which inhibits glutamate resorption (increases extracellular glutamate). Calcium is stored (buffered) in the ER and mitochondria, and then actively pumped back out of the cell. This requires energy
what happens in excitotoxity
excessive glutamate binding causes excessive calcium influx so cell is unable to expel it quickly enough so build up in the mitochondria.
this high calcium causes further glutamate releasee. as well as this proteases and lipase are activated by the Ca causing increased permability. NO synthase requires Ca so more NO which is neurotoxic at high levels.
It also increases arachidonic acid release which increased free radical ad inflammatory mediator production.
Ca build up in mitochondria impairing function
more reactive oxygen species created by dysfunctional mitochondria, increasing cellular damage.
PGE2 and PGD2 are produced from arachidonic acid and cause inflammation
a cell exposed to excessive glutamate will present with
beading axons and swollen cell body
how can an ischaemic brain injury causes exctitoxicty
no oxygen means mitochondria dysfunction so ca build up.
in Parkinson excitotoxicity is implicated in destruction of pigmented cells of substantial nigra
ALS - form of motor neurone disease uses riluzole to slow progression and seems to increase gultamate uptake
in alzeihers memantine slows progression and blocks what channels
NMDA glutamate
what cells absorb glutamate
glial cells - failure would result in excitotoxicity
atrocytes convert it into ATP
