neurosteroid and neuropeptide biosynthetic pathway mechanism of action marketed formulation applications classifications recent findings refrences prepred by jonaid ali a student of m pharm 2nd sem jamia hamdard new delhi.
▪ It is also known as neuroactive steroids.
▪ It is define as the steroids which are synthesized
from brain and produce excitation of neuron
through interaction with ligand gated ion channel.
▪ In brain it is synthesized in glial cells.
▪ It is also synthesized by adrenals,gonads,and
periphery tissues and through blood circulation
reaches to brain and produce action.
▪ Neurosteroid term was coined by French
physiologist Étienne-Émile Baulieu.
▪ physiologist Étienne-Émile Baulieu in 1981
found that brain can itself produce steroids.
▪ The term neuroactive steroid was first
coined in 1992 by Steven Paul and Robert
Classifications and mechanism
• Excitatory neurosteroids: they exert excitatory effect on
Acts as negative modulators of the GABA A receptor , weak
positive allosteric modulator of NMDA receptor and agonist of
sigma 1 receptor.
Have anxiogenic, cognitive and memory enhancing, convulsant,
Example : 3Beta hydroxysteroids such as pregnenolone
sulphate , Dehydroepiandrosterone (DHEA) and
dehydroepiandrosterone sulfate (DHEAS).
Classifications and mechanism
• Inhibitory neurosteroid: they exert inhibitory action on
Acts as potent positive allosteric modulators of GABAA receptor
and possess antidepressant,
ANDROSTANES: androsterone, 3alpha androstanediol,
Classifications and mechanism
▪ OTHER NEUROSTEROIDS
• Endogenous steroids such as pregnenolone,
progesterone,estradiolase are also neurosteroids.
• They do not modulate GABA A or NMDA receptors instead they
affects cell surface receptors and non genomic targets.
▪ Neurosteroids are synthesized from cholesterol, which is converted into
pregnenolone and then into all other endogenous steroids.
▪ Neurosteroids are produced in the brain after local synthesis or by
conversion of peripherally-derived adrenal steroids or gonadal steroids.
▪ They accumulate especially in myelinating glial cells, from cholesterol or
steroidal precursors imported from peripheral sources.
▪ 5α-reductase type I and 3α-hydroxysteroid dehydrogenase are involved
in the biosynthesis of inhibitory neurosteroids, while 3β-hydroxysteroid
dehydrogenase and hydroxysteroid sulfotransferases are involved in
excitatory neurosteroid production
▪ Neurosteroids are synthesized in astrocytes, oligodendrocytes,
Schwann cells, and a few neurons such as Purkinje cells,
hippocampal neurons, and retinal amacrine and ganglion cells.
▪ The rate-limiting step in neurosteroid biosynthesis is the
transport of cholesterol into the mitochondria, which involves the
peripheral-type benzodiazepine receptor.
▪ At the inner mitochondrial membrane, cholesterol is converted to
pregnenolone by action of the P450 cholesterol side-chain
▪ Pregnenolone then passes to the cytosol, where it serves as the
precursor of all neurosteroids.
▪ Modulation of neural plasticity, learning,memory
processes,behavior seizure, responses to stress,anxiety
▪ changes in neurosteroid levels may be involved in the
changes in mood, anxiety, and sexual desire that occur
during puberty in both sexes and during menopause in
▪ Elevated levels of inhibitory neurosteroids, namely
allopregnanolone, can produce paradoxical effects, such
as negative mood, anxiety, irritability, and aggression
• Help in maintaining emotional homeostasis.
• Elevated levels of inhibitory neurosteroids produce paradoxical
effects such as negative mood , anxiety,irritability and
• Role in antidepressant action: fluoxetine and fluoxamine have
found to normalise level of certain neurosteroids at doses that are
inactive in affecting reuptake of serotonin.
• Benzodiazepine effects on neurosteroids :
BZD may influence neurosteroids metabolism by action on
Some BZD inhibits neurosteroidogenic enzymes thus reducing
▪ Several synthetic neurosteroids have been used as sedatives for
the purpose of general anaesthesia for carrying out surgical
procedures.The best known of these are alphaxolone,
alphadolone, hydroxydione, and minaxolone.
▪ The neurosteroid ganaxolone, an analog of the progesterone
metabolite allopregnanolone, has been extensively investigated
in animal models and is currently in clinical trials for the treatment
▪ way of treating catamenial epilepsy with neuroactive steroids
such as ganaxolone during the period of the menstrual cycle when
seizure frequency increases
• Both glial cells and neurons participate in
neurosteroid biosynthesis and metabolism.
• Additional unexpected mechanism of neurosteroid
action is: pregnenolone binds to neural microtubule
associated protein of type 2 (MAP2) and increase the
rate and extent of tubulin polymerisation.
• This play a role in regulating microtubule formation
and thus neuronal plasticity and function.
▪ Extrasynaptic GABA-A receptors are emerging as
novel targets for epilepsy, pain, insomnia, and
mood disorders. Neurosteroids activate
extrasynaptic GABA-A receptor function and thus
are attractive therapeutic agents.
▪ Clinical trials are currently assessing
neurosteroids for the treatment of diverse CNS
disorders, such as epilepsy, SE, FXS,TBI, and
▪ Neuropeptides are small protein-like molecules (peptides) used by
neurons to communicate with each other.
▪ They are neuronal signaling molecules that influence the activity of
the brain and the body in specific ways.
▪ Different neuropeptides are involved in a wide range of brain
functions, including analgesia, reward, food intake, metabolism,
reproduction, social behaviors, learning and memory.
▪ Neuropeptides are secreted from neuronal cells (primarily neurons
but also glia for some peptides) and signal to neighboring cells
▪ The human genome contains about 90 genes that encode precursors
Neurotransmitters consisting of 3-40 amino acids are known
Widely spread in the central nervous system and the
peripheral nervous system.
Have both excitatory and inhibitory actions and work in a
similar way to neurotransmitters.
Many neuropeptides also work as hormones in other parts of
Endorphins: discovered in 1975 by Dr.John Hughes and Dr.
Have a role in memory and learning; sexual activity, and
control of body temperature.
Classical neurotransmitter vs neuropeptides
– released and lower firing rates
– Mediate fast
▪ glutamate release,
receptor activation = fast
– Rapidly replaced – synthesis
occurs in nerve terminals
– Stored in small synaptic
vesicles (50 nm)
– released at higher firing rates
and particularly under burst-
– Mediate slower
▪ Metabotropic receptor
activation = slower
– Degradation after release
– Must be synthesized in cell body
and transported to the terminal
– Stored in large dense core
vesicles (100 nm)
Transgenic Mice Overexpressing NeuropeptideY in Noradrenergic Neurons: A Novel Model of
Increased Adiposity and Impaired GlucoseTolerance
SuviT. Ruohonen, MS1,,4, Ullamari Pesonen, PhD1, Niko Moritz, PhD2, Katja Kaipio, MS1,,4,
Matias Röyttä, MD, PhD3, Markku Koulu, MD, PhD1, and Eriika Savontaus, MD, PhD1,,5
1Department of Pharmacology, Drug Development andTherapeutics
2Department of Orthopedics andTraumatology
From 3Department of Pathology and
4Drug Discovery Graduate School, University ofTurku and
5Clinical Pharmacology,TYKSLAB, Health Care District of Southwest Finland,
Finland significantly increased in comparison with wildtype mice.
Conclusions:The present study shows that even a moderate increase in NPY levels in
noradrenergic neurons leads to disturbances in glucose and lipid metabolism.The OE-
NPYDβH mouse is an interesting new model to investigate the pathophysiology of some key
components of the cluster of abnormalities characterizing the metabolic syndrome.
▪ Paul SM, Purdy RH (Mar 1992). "Neuroactive steroids" (abstract).
FASEB Journal. 6 (6): 2311–22.
▪ Patte-Mensah C, Meyer L,Taleb O, Mensah-Nyagan AG (Feb 2014).
"Potential role of allopregnanolone for a safe and effective therapy
of neuropathic pain". Progress in Neurobiology. 113: 70–8.
▪ Frye CA (December 2009). "Neurosteroids effects and mechanisms
for social, cognitive, emotional,
▪ Neuropeptides and Other Bioactive Peptides: From Discovery to
Function, L.D.Fricker, Morgan & Claypool Publishers, 2012
▪ database of all neuropetides.
▪ Rang & dale pharmacology 7th ed
▪ Basic & Clinical Pharmacology 12th edition by Bertram G.
Katzung,Susan B. Masters & Anthony J.Trevor
▪ Goodman & Gilman’s Pharmacological basis of therapeutics 12th