20230312A - Farm 1 - Introduction To The Pharmacology of The Nervous System

INTRODUCTION TO
THE
PHARMACOLOGY
OF
NERVOUS SYSTEM
FARMACOLOGIA 1
MICF
JORGE GONÇALVES
2024
Neurons
Excitatory
and
inhibitory
synapses
Activation of CREB-dependent gene transcription
a | A few minutes after stimulation. In response to neurotransmitters, calcium flows into the cell through synaptic and extrasynaptic ligand- and voltage-gated
channels, including NMDA (N-methyl- D-aspartate) receptors (NMDARs) and L- and N-type voltage-gated calcium channels (VGCCs). Once the calcium signal
reaches the nucleus calcium/CaM-dependent protein kinase IV (CaMKIV) rapidly phosphorylates CREB
b | Several minutes later. The Ras–MAPK pathway is activated by both NMDARs and L-VGCCs. Activated MAPK phosphorylates and activates pp90 ribosomal
protein S6 kinase (Rsk), then both MAPK and Rsk translocate to the nucleus
Model of the formation of signal-specific transcriptional complexes. Formation
of alternative cofactor complexes with cyclic-AMP-response-element-binding
protein (CREB) and other transcription factors might induce specific genes in
response to different stimuli.
Potencial de ação
Chemical
synapse
Steps at which drugs can alter synaptic
transmission
(1) Action potential in presynaptic fiber;

(2) Synthesis of transmitter;
(3) Storage;
(4) Metabolism;
(5) Release;
(6) Reuptake into the nerve ending or uptake into a
glial cell;
(7) Degradation;
(8) Receptor for the transmitter; 11
Mais um nível de complexidade na abordagem da farmacologia do
(9) Receptor-induced increase or decrease in ionic
conductance;
SNA: os neurónios podem libertar vários transmissores com
(10) Retrograde signaling.
diferentes recetores e locais de modulação farmacológica

(11) Presynaptic receptors (auto or heteroceptors)
Another level of
complexity in
neuropharmacology:
neurons can release
more than one
neurotransmitter from
the same nerve
terminal
Microtubules and Axonal Transport
Microtubules and their motor proteins maintain

axons. Microtubules are formed by the
polymerization of dimers of α-tubulin and β-
tubulin, which dynamically assemble into a
polarized structure that serves as a track for
micro-tubule motor proteins (dynein–dynactin and
kinesins). Genetic defects that affect tubulin,
dynein, dynactin, kinesins, and cargo- associated
molecules such as Rab7 and neurofilament light
(NEFL) are linked to Charcot– Marie–Tooth
(CMT) disease and other neuropathies.
Holzbaur EL, Scherer SS. Microtubules, axonal transport, and neuropathy. N Engl J Med. 2011 Dec 15;365(24):2330-2. doi: 10.1056/NEJMcibr1112481. PMID: 22168648; PMCID: PMC3776444.
Axonal transport defects
Glial Cells in the CNS.
Cells in the CNS. Glial cells and neurons (yellow) closely interact throughout the entire CNS.
Microglia (purple) are the primary immune cells of the CNS surveilling their vicinity.
Oligodendrocytes (cyan) ensheathe neuronal axons. Astrocytes (blue) are in contact with
capillaries and participate in tripartite synapses. NG2 glia (red) connect to nodes of Ranvier and
maintain close proximity to synapses
Protective Functions of
Astrocytes
Linnerbauer M, Rothhammer V. Protective Functions of Reactive Astrocytes Following Central

Nervous System Insult. Front Immunol. 2020 Sep 30;11:573256. doi:
10.3389/fimmu.2020.573256. PMID: 33117368; PMCID: PMC7561408.
Tripartite Synapse
Protective Functions of Reactive Astrocytes
Following Central Nervous System Insult
Linnerbauer M, Rothhammer V. Protective Functions of Reactive Astrocytes Following Central Nervous System Insult. Front Immunol. 2020 Sep 30;11:573256. doi: 10.3389/fimmu.2020.573256.
PMID: 33117368; PMCID: PMC7561408.
•Figure 1 - (A) In babies, neurons do not have any myelin covering them.
•(B) Gradually, as a child grows up, oligodendrocytes wrap axons in myelin. (C) One oligodendrocyte can
myelinate many axons at once. If you were to slice through a myelinated neuron, you would see the myelin
wrapped around the axon in layers. On the right, you can see a real picture of myelin wrapped around axons.
How Oligodendrocytes Help The
Brain Function
•(A) A normal, healthy myelinated neuron in an adult brain.

•(B) When a myelinated neuron degenerates, both the axon and the myelin fall apart and die. (C) If
oligodendrocytes are sick or dying, myelin falls off the axon in a process called demyelination. This can happen in
multiple sclerosis. (D) If the axon is cut or the neuron is otherwise injured, both the axon and myelin fall apart and
die. (E) Neurons can regrow, or regenerate, but regenerated neurons lack myelin on their axons.
Alterações dos oligodendrocitos
Figure 1. Oligodendroglial pathology and possible mechanisms contributing to Multiple system

atrophy. Under healthy conditions, OLs enable saltatory conduction of electrical signals, provide
metabolic and trophic support, and play a role in providing an antioxidant defense system to
neurons.
Dynamic changes of oligodendroglia
during the progression of AD
Figure 2. Dynamic changes of oligodendroglia during the progression of AD. Under healthy conditions, OLs enable saltatory conduction of
electrical signals and provide metabolic and trophic support to neurons. In the AD brain, OLs are vulnerable to neurodegenerative conditions
and acquire a distinct cellular state in response to the changing microenvironment. Under mild Aβ exposure, OLs alter gene expression and
start to exhibit myelin defects. As the disease progresses, defects in OL function and myelin loss become more evident in correlation with
the increased Aβ burden. Perturbation of myelin-axon coupling affects signal propagation as well as metabolic and trophic support. At later
stages with higher Aβ burden, a specific subgroup of OLs express C4b and Serpina3n. Some aspects of the late-stage OLs might be shared
across several NDDs. As AD progresses, microglia also become destructive by releasing neurotoxic inflammatory mediators, such as
cytokines, chemokines, and reactive oxygen and nitrogen species. The changing state of microglia, reflected in part, by their secretory
profile, might play a crucial role in the progression of AD.
Major types of glia in the PNS
1. The myelinating and non-myelinating Schwann cells, which are
associated with peripheral nerves.
2. The satellite glial cells (SGCs) found in sensory, parasympathetic
and sympathetic ganglia.
3. Enteric glial cells (EGCs), which are localised within the ENS
4. Olfactory ensheathing cells (OECs), which reside in both the PNS
and CNS portions of the primary olfactory system.
Schwann cell
Satellite glial cells
Enteric
glia.

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INTRODUCTION TO

(1) Action potential in presynaptic fiber;

diferentes recetores e locais de modulação farmacológica

Microtubules and their motor proteins maintain

Linnerbauer M, Rothhammer V. Protective Functions of Reactive Astrocytes Following Central

•(A) A normal, healthy myelinated neuron in an adult brain.

Figure 1. Oligodendroglial pathology and possible mechanisms contributing to Multiple system

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