neuroinflammation

PRESENTED BY : SARVESH S. MAURYA
F.Y.M.PHARM
UNDER GUIDANCE OF: Mrs. RACHANA SARAWADE
DEPARTMENT: PHARMACOLOGY

INTRODUCTION
 Inflammation is a cardinal host defense response to injury,
tissue ischemia, autoimmune responses or infectious
agents. Classical signs of swelling, redness, heat and pain
are witnessed in all tissues except that of brain as
manifestations of inflammation.
 Neuroinflammation is the inflammation of a nerve or of
the nervous system. It may be initiated in response to a
variety of cues, including infection, traumatic brain injury,
toxic metabolites, or autoimmunity.
 Inflammation in the brain is characterized by activation of
glial cells (mainly microglia and astrocytes).

CENTRAL NERVOUS SYSTEM:NEURONS
 Neurons are highly specialised cells of the body.
 It consists of three main parts- The cell body,single axons,dendrites.
Structurally, neurons are classified according to the number of
processes extending from the cell body:
 Multipolar Neurons
 Bipolar Neurons
 Unipolar Neurons
The cell bodies of most unipolar
neurons are located in the ganglia
of spinal and cranial nerves.
Eg. Purkinje cells, pyramidal cells.
a)purkinje cell b)pyramidal cell

CAUSES AND TYPES OF NEUROINFLAMMATION
 COMMON CAUSES OF NEUROINFLAMMATION
 Toxic Metabolites
 Autoimmunity
 Aging
 Microbes
 Viruses
 Traumatic brain injury
 Air pollution
 Passive smoke
There are two types of Neuroinflammation-
 Acute Neuroinflammation
 Chronic Neuroinflammation.

Acute Neuroinflammation
Acute neuroinflammation usually follows injury to the
central nervous system immediately, and is characterized by
inflammatory molecules, endothelial cell activation, platelet
deposition, and tissue edema.
In limited, acute reactions to injury, in the absence of
blood-brain barrier breakdown, there is the subtler response
.
of the brain's own immune system, composed largely of
rapid activation of glial cells. These responses represent the
other end of the spectrum of CNS injury, where limited
neuronal insults trigger glial cell activation without
breakdown of the blood brain barrier.

Chronic Neuroinflammation
Chronic Neuroinflammation is the sustained
activation of glial cells and recruitment of other
immune cells into the brain. It is chronic
inflammation that is typically associated with
neurodegenerative diseases.
Chronic Neuroinflammation is often associated in
the understanding of CNS disease as opposed to
acute inflammation which is linked with CNS injury.
It is proposed that chronic Neuroinflammation is a
causative factor to the pathogenesis of neurological
diseases and disorders.

CNS IMMUNE RESPONSE AND MAJOR PLAYERS
OF INNATE RESPONSE
 Innate immunity also called natural or native immunity provides the early line of defense
against microbes.
 Innate immunity serves two important functions.
• Innate immunity is the initial response to microbes that prevents, controls, or eliminates
infection of the host.
• Innate immunity to microbes stimulates adaptive immune responses and can influenc the
nature of the adaptive responses to make them optimally effective against different types
of microbes.
 Innate Immune Cell Receptors:
DCs, macrophages and monocytes all possess both surface and intracellular receptors
capable of recognizing pathogen-associated molecular patterns (PAMPs), which are small
molecular patterns associated with specific classes of pathogens and microorganisms.
These specialized patterns are recognized by different families of pattern recognition
receptors (PRRs), and they include TLRs, nucleotide-binding oligodimerization domain
(NOD)-like receptors (NLRs) and RIG-like receptors (RLGs).

 Microglia
Microglia are key players of the immune response in the central nervous system and,
being the resident innate immune cells, they are responsible for the early control of
infections and for the recruitment of cells of the adaptive immune system required for
pathogen clearance.
Fig:Macrophage and microglia activation in the human CNS
When Microglia are activated There are numerous substances are secreted-
 Cytokines
 Chemokines
 Proteases
 Amyloid precursor protein

 Astrocytes
These star shaped cells have many processes and are the largest and most numerous of the
neuroglia. There are two types of astrocytes.
• Protoplasmic astrocytes have many short branching processes and are found in gray matter.
• Fibrous astrocytes have many long unbranched processes and are located mainly in white
matter.
Nutrient support
for neurons
Role of astrocytes Modulation of
neurotransmitter
trafficking
Modulation of
astrogliosis
Modulation
of synaptic
function
Modulation of
cerebral blood
flow
Modulation
of ionic ionic
balance
Modulation of
inflammation

 Cytokines
Cytokines are produced mainly by the leukocytes (white blood cells). They are potent
polypeptide molecules that regulate the immune and inflammation functions, as well as
hemopoiesis (production of blood cells) and wound healing.
There are two major classes of cytokines:
(a)lymphokines and monokines,
(b) growth factors.
 Lymphokines and monokines
Cytokines produced by lymphocytes are called lymphokines, and those produced by monocytes
are termed monokines. Lymphocytes and monocytes are different types of white blood cells.
The major lymphokines are interferons (IFNs) and some interleukins (ILs). Monokines include
other interleukins and tumor necrosis factor (TNF).
Fig:Interleukine molecule.

TNF:
 There are two types of tumor
necrosis factor: TNF-α and TNF-p,
Of the two, TNF-α has been
studied in more detail.
TNF-α is a 157 amino acid polypeptide.
It is a mediator of immune regulation,
including the activation of macrophages
and induction of the proliferation of T
cells. Another TNF-α function is its
cytotoxic effects on a number of tumor
cells.
Fig: TNF-α

 Growth factors
As the name implies, growth factors stimulate cell growth
and maintenance.
The following growth factors are:
• Erythropoietin-Erythropoietin (EPO) is a glycoprotein
produced by specialized cells in the kidneys, It has 166
amino acids and a molecular weight of approximately 36
kDa.
• Colony stimulating growth factors-Growth factors such as
granulocyte macrophage colony stimulating factor (GM-CSF)
and macrophage colony stimulating factor (M-CSF)
are involved in the regulation of the immune and
inflammatory responses. GM-CSF is a glycoprotein with
127 amino acids and a molecular weight of about 22 kDa.

NEUROTROPIC FACTOR RELEASED.
 Neurotrophic factors are a family of proteins responsible for the growth and survival
of neurons during development and for the maintenance of adult neurons. They are
also capable of promoting damaged axons to regenerate after various peripheral and
central nervous system injuries.
 It is secreted by a target tissue (either neuronal or nonneuronal) and acts on the
neurons that innervate that tissue to support their survival or differentiation.
 Neurotrophic factors not only promote the differentiation and growth of developing
neurons and phenotypic maintenance and survival of adult mature neurons but also
represent a potential means of modifying neuronal dysfunction, astrocytic activation
and inflammatory reactions under pathological conditions.
 Families of neurotrophic factors :
 NGF-superfamily-
The NGF-superfamily, originally called the neurotrophins, includes nerve growth
factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-
3),neurotrophin-4 /5 (NT-4/5) and neurotrophin-6 (NT-6).

 GDNF family
The GDNF family, distantly related to the TGF-β superfamily, includes glial
cell line-derived neurotrophicfactor(GDNF) and three structurally related
members called neurturin (NTN), persephin (PSP) and artemin (Art).
 Neurokine superfamily
The neurokine family includes ciliaryneurotrophic factor (CNTF), leukemia
inhibitory factor (LIF), interleukin-6 (IL-6), cardiotrophin-1 (CT-1) and
oncostatin-M.
 Non-neuronal growth factors
Non-neuronal growth factors present in significant concentrations in the
nervous system include acidic fibroblast growth factor (aFGF), also called
FGF-1; basic fibroblast growth factor (bFGF), also called FGF-2; epidermal
growth factor (EGF), insulin-like growth factor (IGF) and bone
morphogenetic protein (BMP).

ROLE OF NEUROTROPIC FACTOR IN
DISEASE PROGRESSION
 Neurotrophic factors regulate numerous neuronal functions in development
and adult life and in response to injury.
 Neurotrophic factors modulate neuronal survival and axonal growth is the
initial rationale for potential clinical correlates to neurodegenerative
disorders and neuronal injury such Alzheimer’s disease, Parkinson’s disease
spinal cord injury.
 Role in neurodegenerative disorders
 The initial clinical correlation to Alzheimer’s disease was made in the 1980s
based on studies on aged animals that showed that cholinergic neurons in the
basal forebrain could be rescued with intra cerebroventricular NGF, resulting in
concomitant improvements in memory function.
 In addition, mutant mouse models of motor neuron disease, in which there was
motor neuron degeneration, demonstrated that BDNF and CNTF could increase
the number of motor neurons and improve motor performance.

NEUROINFLAMMATION:NEUROPATHOLOGICAL AND
CLINICAL CORRELATES
 PARKINSON’S DISEASE:
 The leading hypothesis of Parkinson's disease progression includes
neuroinflammation as a major component.This hypothesis, known as “Braak’s
Hypothesis,” stipulates that Stage 1 of Parkinson's disease begins in the gut.
 The inflammatory response in the gut may play a role in alpha-synuclein (α-Syn)
aggregation and misfolding, If there is a balance between good bacteria and bad
bacteria in the gut, the bacteria may remain contained to the gut. However, dysbiosis
of good bacteria and bad bacteria may cause a “leaky” gut, creating an inflammatory
response.
 The brainstem is vulnerable to inflammation, which would explain Stage 2 of
Braak’s hypothesis, including sleep disturbances and depression.
 In Stage 3 of the hypothesis, the inflammation affects the substantianigra, the
dopamine producing cells of the brain, beginning the characteristic motor deficits of
Parkinson's disease.
 Stage 4 of Parkinson's disease includes deficits caused by inflammation in key
regions of the brain that regulate executive function and memory.

Multiple sclerosis
 Multiple sclerosis is a very common neuroinflammatory disease. It is
characterized by demyelination and neurodegeneration, which contribute to the
common symptoms of cognitive deficits, limb weakness, and fatigue. In multiple
sclerosis, inflammatory cytokines disrupt the blood brain barrier and allow for
the migration of peripheral immune cells into the central nervous system.
 When they have migrated into the central nervous system, B Cells and plasma
cells produce antibodies against the myelin sheath on neurons, degrading the
myelin and slowing conduction in the neurons. Additionally, T Cells may enter
through the blood brain barrier, be activated by local antigen presenting cells,
and attack myelin sheath.
 This has the same effect of degenerating the myelin and slowing conduction. As
in other neurodegenerative diseases, activated microglia produce inflammatory
cytokines that contribute to the widespread inflammation. It has been shown that
inhibiting microglia decreases the severity of multiple sclerosis.

Fig: Synoptic view of the immune response in immune
mediated demyelination of the central nervous system

FUTURE PROSPECTIVE
Drug targets for therapeutic strategy
 Because neuroinflammation has been associated with a variety of
neurodegenerative diseases,there is increasing interest to
determine whether reducing inflammation will reverse
neurodegeneration.
 Inhibiting inflammatory cytokines, such as IL-1β, decreases
neuronal loss seen in neurodegenerative diseases. Current
treatments for multiple sclerosis include interferon-B,
Glatirameractetate, and Mitoxantrone, which function by
reducing or inhibiting T Cell activation, but have the side effect
of systemic immunosuppression.

 In Neurodegenerative disease, the use of non-steroidal anti-inflammatory
drugs decreases the risk of developing the
disease.
 NSAIDs function by blocking conversion of prostaglandin
H2 into other prostaglandins (PGs) and thromboxane (TX).
Prostoglandins and thromboxane act as inflammatory
mediators and increase microvascular permeability.

CONCLUSION
 Neuroinflammation plays an important role in the toxicity and
the progression of the disease process in PD,MS and HD, and
these similarities in the inflammatory responses could be
utilized to develop new therapeutic approaches for their
amelioration. However, the underlying cause of the enhanced
neuroinflammation in each of these diseases still remains
unresolved (i.e. the misfolded proteins), such that these need to
be reduced to remove the stimuli associated with the
inflammatory responses.

neuroinflammation

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