Department of Pharmacology Karnataka college of Pharmacy, Bengaluru, Karnataka, INDIA
Neuroinflammation has emerged as a major contributing factor in the progression of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis. This review highlights the role of inflammatory pathways and immune-mediated mechanisms involved in neuronal degeneration. Activation of microglia and astrocytes leads to the release of pro-inflammatory cytokines such as TNF-?, IL-1?, and IL-6, which contribute to neuronal damage and synaptic dysfunction. Key molecular pathways including NF-?B signaling, NLRP3 inflammasome activation, oxidative stress, mitochondrial dysfunction, and abnormal protein aggregation are critically involved in disease pathogenesis. Protein aggregates such as amyloid-? and ?-synuclein further stimulate chronic inflammatory responses, accelerating neurodegeneration. Current therapeutic approaches mainly provide symptomatic relief and include cholinesterase inhibitors, dopamine agonists, immunomodulators, and antioxidant therapies. However, these treatments are limited by poor blood–brain barrier penetration and inability to halt disease progression. Emerging therapeutic strategies targeting neuroinflammation, including cytokine inhibitors, NLRP3 inflammasome blockers, monoclonal antibodies, stem cell therapy, gene therapy, and nanotechnology-based drug delivery systems, show promising potential as disease-modifying interventions. Understanding the molecular basis of neuroinflammation may facilitate the development of personalized and effective therapeutic approaches for neurodegenerative disorders in the future.
Neurodegenerative illnesses comprise a diverse range of diseases that share as a common feature a progressive loss of the nervous system and its functional abilities, characterized by a general impairment of mental and physical functioning which eventually causes cognitive and motor disabilities. The most common of these are Alzheimer, Parkinson, multiple sclerosis and amyotrophic lateral sclerosis and they are known to pose a major health burden to the world. These disorders are widely prevalent and are closely linked with increasing populations of people of advanced age making them one of the major causes of concern to all healthcare systems globally5. Over the past few years, neuroinflammation has become one of the key mechanisms of pathogenesis of neurodegenerative diseases. Neuroinflammation is the stimulation of the brain’s innate immunological response mainly conducted by microglia and astrocytes, to injury, infection, or the deposition of misfolded proteins6. Though acute inflammatory reactions can come into play in the early stages and have protective roles in the elimination of pathogen and cell debris, chronic and unregulated inflammation has an adverse effect on neurons and disease progression7. The activation of microglia is a central element in the process of the development and maintenance of neuroinflammatory reactions. Activated microglia secrete numerous pro-inflammatory mediators, such as tumor necrosis factor-alpha (TNF- 0), interleukin-1 beta (IL-1 -), interleukin-6 (IL-6) that worsen neuronal damage and synaptic dysfunction8. Also, the astrocytes aid in the inflammatory environment by producing chemokines and cytokines that improve immunological signaling9. In the central nervous system. One of the most fascinating aspects of neurodegenerative disease is the presence of abnormal protein, such as amyloid beta in Alzheimer’s disease and ?-synuclein protein in Parkinson’s disease. Damage associated molecular patterns (DAMPs) are protein aggregates that cause immune response and result in persistent inflammation10. Furthermore, activation of intracellular signaling nuclear factor-kappa B(NF-KB)and the NLRP3inflammation form two essential pathways to control the expression of inflammatory genes and the release of cytokines11. Neurodegeneration is mostly caused by the intimate connections between oxidative stress, mitochondrial failure, and neuroinflammation. Reactive oxygen species (ROS) over production causes lipid peroxidation the death of the cells and DNA damage.
Objective13
Major Diseases:
Prevalence:
Importance of study:
Knowledge of neuroinflammation yields
Mechanism of Disease: Molecular Pathways.
There are a number of interconnected molecular means of neuroinflammation:
1. Microglial Activation24
Initiated by trauma, toxins or protein aggregates.
Produces the pro-inflammatory cytokines TNF-a, IL-1b, and IL-6. The primary microglia are innate immune cells which live in the central nervous system to regulate inflammation in the brain. There are several different types of activated microglia, some of which are beneficial and some of which are detrimental. CNS microglial activation can be divided into two opposing phenotypes: the anti-inflammatory M2 phenotype and the pro-inflammatory M1phenotype (Figure1)
1. Microglia that express the nuclear factor-kB (NF-kB) and inducible nitric oxide synthase (iNOS)pathways produce TNF-?, interleukin-1 beta (IL-b), and other pro-inflammatory mediators, interleukin-6, superoxide, ROS, and nitric oxide (NO) all cause the normal activation type of microglia, referred to as M1 microglia6. Interleukin-4 (IL-4) interleukin-13 (IL-13) and interleukin-10 (IL-10)/transforming growth factor-beta (TGF-B) signalling, also referred to as alternative activation and acquired deactivation, respectively, trigger a variety of activation programs in M2 microglia. As long as the underlying clinical insult occurs in system circulation and peripheral organs, the question of how microglia alter phenotypes is crucial.
Figure 1: Microglial Activation
2. NF-κB Pathway25
Key controller of the inflammatory process.
Increases the inflammatory genes transcription14. A class of transcription factor protein complexes known as NF-kappa-light-chain-enhancer of activated B cells (NF-kappaB) controls DNA transcription, cytokine synthesis, and cell survival. NF-kB is recognised to be essential to the immune response to an infection and is expressed in almost all in animal cell types. Improper regulation of NF-kB has been linked to immunological development, viral infection, septic shock, cancer, and inflammatory/autoimmune diseases. It has also been discovered that NF-kb plays a role in memory and synaptic plasticity.
Structure:
NF-KB proteins the N-terminus of every protein in the NF-KB family has a Rel homology domain. The transactivation domain proteins of NF-kB are found in the C-termini of RelA, RelB, and c-Rel. On the other hand, the mature p50 and p52 proteins are formed by the regulation of the big progenitors of NF-kB1 and NF-kB2 proteins, which are around 105 and 100 nm in size, respectively. P105 and P100 are processed by the proteasome pathway. which is their C-terminal regions preference degradation which contains ankyrin repeats. In contrast to the tight regulation of the generation of p52 out of p100, p50 is generated out of constitutive processing of p105. The p50 protein has been suggested to be a transcriptional repressor when it binds to κB elements as a homodimer, and the process of p50 production is indeed confounding the interpretation of p105-knockout studies, where the genetic manipulation is removing an I 0 B (full-length p105) and a probable repressor.
Figure 2: NF-κB Pathway
3. Activation of NLRP3 Inflammasome26-29
Causes IL-1β and IL-18 production.
Causes chronic inflammation.
1.Inflammasome NLRP3 (Signal 1) Priming:
In the case of macrophages, NLRP3 activators are not sufficient to trigger the activation of inflammasomes but also these need to be activated by a priming signal (signal 1). Priming stimuli, including the transcription factor NF-+ must be activated by ligands to toll-like receptor (TLRs), NLRs (NOD1, NOD2), or cytokine receptor ligands. NF- kB enhances the expression of pro-IL-1B, which resting macrophages do not generate, and NF-LRP3, which is thought to be present at insufficient levels to cause inflammasome activation in resting macrophages. Conversely, pro-caspase-1,pro-IL-18, and ASC expression levels appear to be unaffected by priming cues. Furthermore, in response to TLR ligands, NLRP3 and pro-IL-1B production is regulated by MyD88 and TRIF, two signaling molecules that orchestrate the NF-KB signalling pathway. According to recent research, caspase-8 and FADD, in addition to the NLRP3 signalling molecules, are also required for NLRP3 induction during priming phase, regardless of their apoptotic activity.
2. Activating the NLRP3 Inflammasome (Signal 2)
The possible variety of activating stimuli after this priming step is quite broad, which include K+ ionophores, heme, particulate particles, and ATP. pathogen-associated RNA as well as components and poisons produced by bacteria and fungi. Since none of these agonists have been shown to directly interact with NLRP3, it is hypothesised that they share a cellular signal due to their differences. The NLRP3 inflammasome is currently shown to be activated by a number of molecular and cellular signals in response to stimuli NLRP3, including mitochondrial, influx malfunction and lysosomal degradation and reactive oxygen species (ROS) generation.
Figure 3: NLRP3 Inflammasome of activation.
4. Oxidative Stress 30, 31, 32, 33, 34, 35
Too much ROS, or reactive oxygen species destroys neurons. The disparity between pro-oxidants and antioxidants in the body whereby the pro-oxidants activity is dominant as compared to antioxidants activity is referred to as oxidative stress The consequence of the reactive species is the oxidative damage of biomolecules in the event of oxidative stress. The cells are compartmentalized because of the complexity of the human body which enables oxidation micro environments which experience varying degrees of oxidative stress. The unique design and function of the organs within the human body also lead to opposing oxidative stress levels, which complicates the efforts to classify and treat the body's oxidative stress, along with the pathogenesis it leads to Oxidative stress is associated with many negative health disorders including neurodegenerative disorders, inflammatory disorders, cardiovascular disease, diabetes, allergies, immune dysfunction, aging and cancer (Fig. 4) The products of the mitochondrial metabolism in the human body are known as reactive species. The most common form of reactive species is the reactive oxygen species (ROS). Human body needs ROS to signal in the processes, including the one that entails the killing of viruses and bacteria, and then elimination of the reactive species eventually by the body occurs. Nevertheless, in cases where the ROS levels are too high in the body, it causes oxidative damage to RNA and DNA, lipids, and proteins. In particular, there are genetic mutations and cancer that can be induced by DNA damage. Moreover, cancer cells have high ROS requirements due to their augmented metabolic requirements.
Figure 4: Oxidative Stress
5. Mitochondrial Dysfunction 36,37,38,39,40,41
Defective energy generation and hyper apoptosis.
The impairment of the ETC components (Complexes I-V) decreases the ATP production, which leads to the lack of energy to perform cellular processes.
Overproduction of proteins reactive oxygen species (ROS), mitochondrial membranes, mtDNA, creating a vicious cycle of deterioration.
c) Dysregulated Calcium Homeostasis:
Mitochondria lose their ability to regulate calcium appropriately and accumulate it, resulting in calcium overload and activation of cell death (apoptosis).
d) Low Quality Control (Mitophagy):
The inability of the system to eliminate damaged mitochondria (mitophagy) leads to the accumulation of dysfunctional organelles into the cell.
e) mtDNA Instability:
Changes in mitochondrial DNA (mtDNA) mutations or deletions destroy the production of essential proteins required in the functioning of mitochondria.
Figure 5: Mitochondrial Dysfunction
6. Protein Aggregation 42,43,44,45,46,47,48,49,50
Figure 6: Protein Aggregation
Alzheimer’s Disease51
Figure 7: Alzheimer’s disease
Parkinsons disease52
Parkinson disease is a progressive illness of the neurological system. It affects nerve cells (neurones) in certain brain regions to weaken, damage, and die resulting into symptoms such as movement problems, tremor, stiffness, and poor balance. Walking, talking, and other simple tasks can become challenging to people with the Parkinson disease (PD) as the symptoms progress.
A chronic neurological condition is multiple sclerosis (MS). It MS is an autoimmune disease, which damages the immune system, which should protect us against viruses, bacteria and other harmful things, attacks healthy cells. MS symptoms normally occur among young adults, ages 20-40.
Figure 8: Parkinson’s Disease
Multiple Sclerosis 53
Figure 9: Multiple Sclerosis
ALS 54
Clinically approved Drugs and Mechanism of Action [55,56,57,58]
|
Drug |
Disease |
Mechanism |
|
Donepezil |
AD |
Inhibits acetylcholinesterase. |
|
Memantine |
AD |
NMDA receptor antagonist. |
|
Levodopa |
PD |
Dopamine replacement. |
|
Interferon-2 |
MS |
Immunomodulation |
Shortcomings of Existing Therapy
Therapeutic Perspectives:
New Therapeutic Targets and Clinical Perspectives:
Novel Therapeutic Targets: Neuroinflammation has emerged as a useful disease-modifying therapy in neurodegenerative diseases. Microglial activation pathways, cytokine signaling, and inflammasome parts are the major molecular targets. Specifically, NLRP3 inflammasome inhibition has demonstrated a lot of promise in lessening neuroinflammatory reaction and neuronal harm59. On the same note, Additionally, NF-0 B, or nuclear factor-kappa B, signaling has been adjust to dampen the pro-inflammatory gene transcription60. The other target of interest is the TREM2, a triggering receptor produced on myeloid cells that regulates microglial activation and phagocytosis. Enhanced TREM2 can be useful in the disease like Alzheimer to ameliorate clearance of pathological protein aggregates61. Also, the use of chemokine receptors CCR2 and CX3CR1 has also been promising in controlling the recruitment of immune cells and neuroinflammation62.
New Drug Candidates and Molecules:
A number of new molecules are being investigated as anti-neuroinflammatory. NLRP3 small-molecule inhibitors, including MCC950, have shown intensive neuroprotective efficacy in preclinical models in terms of cytokine generation and inflammasome activation63. Aducanumab monoclonal antibodies that target amyloid-beta have been created to inhibit protein aggregation and other related inflammatory reactions in Alzheimer disease64. Moreover, alpha-synuclein-targeting agents are under development as a Parkinson's disease treatment to inhibit aggregation and microglial stimulation65. Natural substances like resveratrol and curcumin have also demonstrated antioxidant and anti-inflammatory qualities by modification of various signaling pathways, one of which is the transforming the NF-KB and MAPK66.
Clinical Trials:
The recent clinical trials have been on immunotherapy and anti-inflammatory measures. Anti-amyloid drugs such as monoclonal antibodies have advanced to late clinical trials in the management of Alzheimer's disease with mild effects on the disease's progression Inflammatory cytokines targeting drugs, including TNF-alpha-inhibitors, are also under consideration to reduce neuroinflammation and improve neurological outcomes67. In addition, cell therapies using stem cells are being clinically tested to have the capability of regulating the immune system and neuronal regeneration68.
Experimental Studies:
Preclinical investigations in animal models have given solid evidence in attacking neuroinflammation. Blockage of microglial stimulation has been reported to prevent neuronal death and enhance cognitive capabilities of the experimental models of Alzheimer and Parkinson diseases. There are efforts in the area of gene-editing to control inflammatory genes expression and correct disease-related mutations including CRISPR/Cas969. Drug delivery systems based on nanotechnology are also under development to increase the penetration of blood-brain barriers and targeted delivery of the anti-inflammatory agents70.
Future Perspectives:
The future therapeutic approaches must employ the use of early intervention and personalized medicine. The multiple pathway combination therapies such as inflammation, oxidative stress and protein aggregation can be offered with a better chance to manage the disease71. Discoveries in the field of biomarkers e.g. inflammatory cytokines and image will help in early diagnosis and monitoring of progress in treatment72. More advanced methods of artificial intelligence and precision medicine are also likely to transform the procedure of drug discovery and treatment interventions in the neurodegenerative diseases.
Clinical Relevance73,74,75,76,77
Targeting neuroinflammation has clinical advantages, such as reduction of the disease progression and patients' quality of life. Anti-inflammatory medication can be utilized to supplement the existing symptomatic therapies and has disease-modifying effects. Knowing patient-specific inflammatory profiles can provide individual treatment plans, reduce adverse effects and increase the therapeutic benefit.
Discussion78,79
Neuroinflammation is a two-sided sword that has benefits as well as adverse outcomes. General chronic activity causes neural injury and pathology. Even though there are therapies in place that are symptomatic, they do not prevent the progression of the disease. Inhibiting individual inflammatory pathways like NF- -B and NLRP3 inflammasome is a potential strategy. Incoming research must be conducted on the topics of early diagnosis, personal medicine, and combination therapy.
CONCLUSION80,81,82,83
One important aspect of the pathophysiology of neurodegenerative diseases is neuroinflammation. Knowing the molecular pathways provides new prospects of therapeutic intervention. Regardless of the progress in the use of the drug therapies, disease-modifying therapies are still needed. The inflammatory pathways are potential targets that can offer effective mechanisms to delay or inhibit neurodegeneration.
REFERENCES
doi: 10.1038/s41582-020-00435-y
doi: 10.1038/s41582-020-00435-y
Darshan R.*, Kusu Susan Cyriac, Role of Neuroinflammation in Neurodegenerative Diseases: Therapeutic Perspectives, Int. J. of Pharm. Sci., 2026, Vol 4, Issue 5, 5922-5938. https://doi.org/10.5281/zenodo.20344411
10.5281/zenodo.20344411
