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Question

what type of receptors showed a marked decrease in some schiz patients?

Answer 1

* M1R decreased in all regions, in particular hippocampus caudate-putamen and DLPFC * consequence is abnormarl GP recruitment of M1 * no evidence that drugs affected the number of M1Rs * 25% patients lost 75% of cortical M1Rs * No change in M2, M3 or M4Rs * M1R = cholinergic = muscarinic receptor deficient (MDR)

Answer 2

* 25% have lost 75% of cortical M1Rs * 25% on average given higher levels of anti-psychotic drugs --\> resistant group? *

Answer 3

drugs havent caused decrease * patients with low M1R are more agitated therefore more likely to be give BZD * GABA system does not appear to affect MRs microRNAs - one targeting M1, one does not * level of microRNA increases in patients who have lost M1Rs as microRNA blocks translation * loss of mRNA by blocking it with microRNA

Answer 4

* xanomelin - M1 agonists, improved cog deficiency * allosteric M1 modulators

Answer 5

adult DCNS neurons are post-mitotic * do not divide - is lost it is for good * neuronal stem cells mostly inact in adult - not many born (exp olfacotry + hippo) * dead neurons are replaced by glial cells -scar formation many CNS neurons are extremely large * very large SA - big target, more exposure to toxins * energy intensive, dep on high O2 supply * many neurons use Fe3+ for NT synthesis -formation of ROS polarised cell mebranes * activated by depol - release NT, IC Ca2+ * damage often causes prolonged depol - disrupts neuronal function

Answer 6

* programmed cell death * extrinsic and intrinsic signal activate proteases * plasma membrane blebbing occurs * apoptotic neurons display "eat me" signals on surface * mac's move in to dispose of cell in orderly manner without eliciting an inflammatory response

Answer 7

* unprogrammed cell death * often elicits inflam response * caused by enzymes released from lysosomes that digests cell * cell swell * damage to neuron may compromise lysosome membrane direcetly or set off chain reaction * may harm nearby cells * removal of cell debris is difficult as cells dont have "eat me " signals to attact phagocytes to engulf neuron

Answer 8

* absence of survival factors * DNA damage * oxidative stress * death receptor ligands

Answer 9

* hypoxia, ischemia * depletion of ATP * prolonged membrane depolarisation * disrupted Ca2+ control * activatin of proteases * damage to membrane * local imflammation/ damage to neighbouring cells

Answer 10

* NOS produces NO and RNS (reactive nitrogen species) + ROS --\> cell membrane lipid and protein oxidation and DNA base modification

Answer 11

1. post-fertilisation 2. pre-implanatation 3. implantation --\> gastrulation 4. organogenesis 5. foetal period

Answer 12

* as brain develops ethanol can cuase FAS --\> dysmorphorism, intellectual defects * tobacco smoke --\> developmental disease and morbidity * nicotine = teratogen * teratogen exposure --\> all or nothing efefct in pre-embryonic phase

Answer 13

* medications taken during 3-8 week phase have the greatest potential to induce gross malformations by affecting organogenesis * type of malformation dep on which organs are most susceptible at the time * folate deficiency is associated with neural tube defects (closure) * anti-seizure med's are folate antag's (methotrexate, 5-fluruorcil) * folate function as carbon donor in formation of serine from glycine - affects purine and pyrimidine bases and tRNA(indirect)

Answer 14

* altered energy source * altered nucleic acd function/integrity * change memrbane characterisitcs * enzyme inhibition * mutation

Answer 15

* PNS axons can regenerate to re-establish some lost connections * some limited CNS axon sprouting but little axon regeneration * dendrites can regenerate to reform new connections * recrutiment of alternate undamaged neurons to perform new functions (if regen not successful)

Answer 16

* it is product of DA that promotes cell death * XS DA --\> ROS * DA forms quinone with Cys residues on proteins (cell damage) * requried Fe3+ for synthesis * metabolised by MAO-B = ROS * DA neuron in high density

Answer 17

* MPTP - toxin affect neuron cell body * produces Parkinson's symtomes * depletes DA terminals * lipid-soluble, cross BBB * enters astrocytes, converted to MPP+ by MAO-B * MPP+ accumulates in DAergic cells of substantia nigris cia DAT re-uptake system * MPP+ enters mitchondria, block respiration --\> energy depletion --\> neuronal death

Answer 18

* MAO-B inhibitors - block MPTP--\> MPP+ * DAT blockers - block MPP+ uptake * PARP-1 knockout mice have decreased sensitivity to MPTP+, suggesting PARP inhibitors may be used in treatment of PD

Answer 19

* accumulates in membrane of oligodendrocytes and disrupts the myelin sheath in CNS white-matter * De-myelinated neurons are slower, AP arrive out of synch * lipid soluble

Answer 20

* damages neurofilaments and cross-linked cytoskeleton proteins which disrupts AP at nodes of Ranvier * axon pathology shows from distal --\> proximal end

Answer 21

Acute * low exposure - alterations of cognitive and psychomotor functions (reverible) * high - headaches, ataxia, nauses, euphoria (mostly reversible) * very high - coma, loss of consciousness, deah Chronic: impairment of memory and learning skills, irritability, personality change

Answer 22

* peripheral neurological defects * sensorimotor polyneuropathy (n-hex) * demyelinating polyneuropathy (nitrous oxide) * extreme weakness (nit) may be related to inactivation of vitamine B12

Answer 23

* axonal transport: MT (fast) and neurofilaments (slow) toxin s * colchicine - binds tubulin and prevents polymerisation * vincrisstine - prevents MT formation * nocodazole - causes depolymerisation of MTs * mercury - bind beta sub's of tubulin and disrupts MT formation and transport

Answer 24

* metals are frequently bound to proteins for transport, storage and limit their redox reactivity * lead can replace Ca2+ in bone because both exist as 2+ state and have similar radii so can fit into same pocket * pathology: oedema of brain to extravasion of fluid from capillaries, neuronal death and gliosis * recovery: epilepsy, mental retardation, blindness * lead have pronounced effects on development of CNS and produces cognitive impairments, affects glu-transmission and DAergic function (critical for learning and mem)

Answer 25

* competes/sub's Ca2+ and disrupts Ca2+ homeostasis * stimulates Ca2+ release from mitochondria * damages mitocondia and membranes * accumulates in brainastrocyes etc. (glials) * absorption of Pb from GI tract greater in children, Pb crosses intestinaly cells via Ca2+ uptake systems (upreg in kids) * highest concentration in hippo, cerebellum and cerebral cortex * once deposityed lead to eliminated very slowly - half life of 2 years in brain

Answer 26

* acute - CNS depression, vasodilation, hypoglycaemia * chronic - fatty liver, alchoholic hepatitis, cirrhosis * developmental - low birth weight, poor muscle coordination, mental deficiency * metabolism - by alcohol dehydrogenase (ADH) - toxicity due to metabolite acetealdehyde and formic acid

Answer 27

* nerve growth factor (NGF) - promotes survival of sympathetic neurons (PNS), sensory neurons (PNS), cholinergic neurons (CNS * brain-derived neurotrophiv factor (BDNF) - promotes survival of sensory neurons, motor neurons, DAergic neurons in CNS * Neurotrophin-3 (NT-3) - promotes surival of sensory neurons (CNS) * NT-4/5

Answer 28

* target-derived: NGF in targets on sympahetic neurons, BDNF in muscles * paracrine sources: BDNF up-regulated in Schwann cells after axonal lesion * autocrine: BDNF in dorsal root ganglion promotes dorsal root ganglion survival

Answer 29

* Trk family, receptor TK's - high affinity binding * p75 - low affinity binding

Answer 30

* survival/differentiation signals * trkA, trkB, trkC * EC ligand binding domain * single TM domain * cytosoic TK activity NGF--\> trkA BDNF and NT-4/5 --\> trkB NT-3 --\> trkC (small amount to others)

Answer 31

1. neurotrophin binds 2 trk molecule 2. NT-trk complex bind 2nd 3. homodimerisation of receptor 4. activation of intrinsic TK domain 5. autophosphorylation of specific Tyr 6. recruitment of SH2-fomain containing proteins from cytosol e.g. PLCγ

Answer 32

* forms complex with trk or signals itself (Apoptosis) apoptosis * antisense to p75 causes age-dependent survival/apoptosis rat sensory neurons * NGF --\> apoptosis rat retinal neurons expressing p75 not trkA * p75 KO --\> loss of sympathetic and sensory neurons

Answer 33

ciliary neurtophic factor (CNFT) * a cytokine related to IL-6 * promotes surival of motor neurons, ciliary neurons, sympathetic neurons * not found in neuronal targets, present in schwann cells * acts as lesion factor. damage --\> release and CNFT surrounds nerve to protect it

Answer 34

* no intrinsic TK domain * recruits IC TK upon ligand binding * CNFT receptor complex: * Gp130 + CNTFRα (no IC domain) + LIFRβ→ multimerisation (with ligand) * complex recruits kinases e.g. JAK/TYK which phosphorylate complex

Answer 35

* in neurodegenerative diseases e.g. motor neuron disease (MND), PD * characterised by loss of neuron populaitons * BDNF and MND preclinical evidence * ability to prevent peripheral nerve degen following axotomy * arrest of disease in some mouse models * shown to have lack of benefit (pharmacokinetics, disease related) * CNFT also shown to decrease neuronal death - withdrawn due to toxicity

Answer 36

NGF and pain * provokes pain --\> hyperalgesia * inhibition of NGF decreases pain and hyperalgesia * NGF antag's = analgesics? * side effects - peripheral neuropathy etc BDNF used to treat depression and schizophrenia

Answer 37

* blocks catecholine reuptake transporters therefore prolonging DA in synapses * activates limbic system - euphoria as well as rebound depression after DA depleted * activates BG - hyperactivity, rebound hypoactivity * increase DA at D1 and D2 receptors (satiety and craving) * serotonin R's involved in feeling warmth/love with MDMA, * decrease serotonin receptors with chronic use (down reg)

Answer 38

* TLR and IL-1 signalling - detect pathogens * macrophages have an abundance of TLR transcripts as wella s glial cells (in brain) * activation of TLR drive pro-inflammatory cytokines * MyD88 = adaptor protein * all require MyD88 except TLR3

Answer 39

* MyD88-signalling may be protective * KO MyD88 so all TLR not working (exp TLR3) --\> massive stroke compared to control * unexpected because TLR plays role in inflammation--\> death * in vitro - determinal, in vivo MyD88 signalling is protective * damaged brain signals for mediators invasion * TLR det release of cytokines and factors MyD88 in haematopoietic cells det infarct volume * haematopoietic cells play protective role in brain after stroke using TLRs and MyD88 sig * MyD88 in haema cells det cellular infiltration and therefore infarct volume * MyD88 -/- means no invasion, large infarct IL-10 (is AI cytokine) decreases damage of stroke, it is under control of MyD88. T-regulatory cell release it

Answer 40

* embolism break off and entery artery * most likely occludes mid-cerebral artery * MCA pefuses a lot of area in the brain

Answer 41

* hypertension: ACEI with diuretics * lipid lowering: elevated LDL increases risk of stroke * diabetes type II: co-morbidity, increases risk

Answer 42

energy failure ⇒ ATPase Na+/K+ not functioning ⇒ depolarisation ⇒ Glu release ⇒ Ca2+/Na+ entry ⇒Ca2+ activates enzymes (NOS)⇒free radicals ⇒mediator release, DNA damage, mitochondiral damage⇒VISCIOUS CYCLE ⇒Na+ causes swelling

Answer 43

* lipid peroxidation (arachondic acid cycle, from phospholipid bilayer) * free radicals influence signal transduction and therefore how cell behaves * many processes occur - targeting one will not prevent the damage * high levels of Gpx in brain, low lebels of CAT * Gpx -/- mice: massive infarct size, lots of H2O2, oxidative stress plays huge role in injury

Answer 44

* NFKB = major TF in oxidiative stress * oxidants --\> more NKFB --\> more adhesion molecules i.e. mediators (e.g. ICAM) = BAD * NKFB up-regulated; ICAM up-reg; Leukocytes roll and adhere more avidly --\> bigger stroke * higher in smokers, drinkers

Answer 45

* not as detrimental as previously though * post-ischmeic WT has more leukocyte recruitment in venules then Gpx -/- (more oxidative stress) * evidence that they may not be damaging as thought - MAb's that target selectins and ICAM so leukocytes cannot adhere

Answer 46

* T-PA i.v. is beneficial for ischemic strokes - 3 hour window * early admission to hospital with stroke unit is critical * hypothermia: * may decrease damage from excitotoxins, inflammation, free rad's and necrosis * shivering can be detrimental - but muscle relaxants may also stop breathing * development of safer endovascular heat exchangers + anti-shivering protocols which avoid sedation * steroid - no imporvement in trials * Glu-NMDA antags - all trials failed

Answer 47

* prevention of strokes for those who have already suffered one * anti-platelet/anti-thrombotic agents: * aspirin decreases risk * Clopidogrel superior to aspirin? * dipyimadole in patients who have failed aspirin * combination? * athersclerosis - anti platelet * cardioembolic - warfarin * surgical prevention: carotid endarterectomy in patients with extracranial carotid artery disease - trials * intracranial stenosis - trials * prevention = most cost effective * understanding subtye of stroke imp in development 2o prevention stratergies

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