Neuroinflammation in Neurodegenerative Disorders: Current Knowledge and Therapeutic Implications
Abstract
:1. Introduction
2. General Causes of NDs
3. Common NDs and Their Treatment Approaches
3.1. Alzheimer’s Disease (AD)
3.2. Parkinson’s Disease (PD)
3.3. Amyotrophic Lateral Sclerosis (ALS)
3.4. Huntington’s Disease (HD)
4. Drugs Targeting Neuroinflammation in NDs
4.1. AD
4.2. PD
4.3. ALS
4.4. HD
5. Conclusions and Future Prospective
Author Contributions
Funding
Conflicts of Interest
References
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Neurodegenerative Disorders | Drug Class | Drug Name | Dosage Form | Side Effects | References |
---|---|---|---|---|---|
AD | Cholinesterase inhibitors | Donepezil | Tablet | Nausea, vomiting, diarrhea, anorexia, weight loss, muscle cramps, insomnia, fatigue | [76,77,78] |
Rivastigmine | Capsule, transdermal patch | Nausea, vomiting, diarrhea, anorexia, weight loss, indigestion, fainting, muscle weakness | [76,78,79] | ||
Galantamine | Tablet, capsule, oral solution | Nausea, vomiting, diarrhea, decreased appetite, weight loss, headache, dizziness | [76,78] | ||
N-methyl-D-aspartate (NMDA) antagonist | Memantine | Tablet, capsule, oral solution | Diarrhea, dizziness, headache, constipation, confusion | [76,78] | |
Atypical antipsychotic | Brexpiprazole | Tablet | Common cold symptoms, dizziness, shaking, increased appetite, weight gain, high blood sugar, stroke | [76] | |
Disease-modifying immunotherapy | Lecanemab | Intravenous infusion | Brain swelling and bleeding, headache, confusion, dizziness, nausea, vomiting, cough, diarrhea, visual changes, body aches, fever, fatigue, slow or fast heartbeat, loss of appetite | [76] | |
Aducanumab | Intravenous infusion | Brain swelling and bleeding, headache, confusion, dizziness, falls, diarrhea, visual changes | [76,78] | ||
PD | Dopamine precursor with metabolic inhibitor | Levodopa/carbidopa | Tablet (IR, ER), capsule, enteral suspension, inhaler | Nausea, vomiting, low blood pressure, anorexia, confusion, dizziness, dyskinesia, nervousness, hallucinations | [78,80] |
Dopamine agonists | Pramipexole | Tablet | Dizziness, drowsiness, confusion, hallucinations, nausea, low blood pressure, leg swelling, sleep attacks, compulsive behaviors like gambling, vision problems, tiredness | [78,80] | |
Ropinirole | Tablet | Dizziness, drowsiness, confusion, low blood pressure, leg swelling, nausea, vomiting, constipation, dry mouth, headache, tiredness, compulsive behaviors like gambling | [78,80] | ||
Apomorphine | Subcutaneous injection, sublingual film | Injection: Allergic reactions, dizziness, drowsiness, low blood pressure, leg swelling, confusion, sleep attacks, nausea, headache, compulsive behaviors like gambling Sublingual: nausea, mouth swelling, pain and sores, dizziness, sleepiness | [78,80] | ||
Rotigotine | Transdermal patch | Nausea, vomiting, dizziness, drowsiness, confusion, tiredness, headache, low blood pressure, skin rashes, sleep attacks, compulsive behaviors like gambling | [78,80] | ||
Bromocriptine | Tablet, capsule | Blurred vision, double vision, nausea, vomiting, low blood pressure, headache, dizziness, drowsiness, constipation, loss of appetite, tiredness | [81] | ||
Monoamine oxidase-B inhibitors | Rasagiline | Tablet | Nausea, dry mouth, dizziness, drowsiness, strange dreams, constipation, stomach/abdominal pain, heartburn, weight loss, may worsen dyskinesia | [78,80] | |
Selegiline | Tablet, orally disintegrating tablet, capsule | Nausea, dry mouth, dizziness, constipation, abdominal pain, insomnia, headache, may worsen dyskinesia | [78,80] | ||
Safinamide | Tablet | Nausea, dry mouth, dizziness, constipation, insomnia, may worsen dyskinesia | [78,80] | ||
Catechol-O-methyltransferase inhibitors | Entacapone | Tablet | Diarrhea, discolored urine, potentiate levodopa related side effects, especially dyskinesia and confusion | [78,80] | |
Tolcapone | Tablet | Diarrhea, discolored urine, enhanced side effects of levodopa especially dyskinesia | [78,80] | ||
Opicapone | Capsule | Dizziness, drowsiness, dyskinesia, weight loss, constipation, low blood pressure | [78,80] | ||
Anticholinergics | Benztropine | Tablet | Confusion, hallucinations, memory issues, blurred vision, dry mouth, nausea, constipation, flushing, urinary retention | [78,80] | |
Trihexyphenidyl | Tablet, elixir | Confusion, hallucinations, memory issues, blurred vision, dry mouth, urinary retention | [78,80] | ||
Adenosine A2A antagonists | Istradefylline | Tablet | Dyskinesia, hallucinations, dizziness, insomnia, nausea, constipation | [78,80] | |
N-methyl-D-aspartate (NMDA) antagonist | Amantadine | Tablet, capsule, syrup | Dizziness, hallucination, confusion, dry mouth, nausea, constipation, insomnia, urinary retention, peripheral edema | [78,80] | |
ALS | Glutamate-receptor antagonist | Riluzole | Tablet, oral suspension, oral film | Dizziness, drowsiness, weakness, nausea, vomiting, increased blood pressure, numbness/tingling around the mouth | [78] |
Free radical scavenger | Edaravone | Oral suspension, IV infusion | Bruising, gait disturbances, tiredness, headache | [78] | |
Neuronal apoptosis inhibitors | AMX 0035 (Sodium phenylbutyrate and Taurursodiol) | Oral suspension | Diarrhea, nausea, abdominal pain, decreased appetite, upper-respiratory-tract infections, dizziness, drowsiness, tiredness | [82] | |
Antisense oligonucleotide | Tofersen | Intrathecal injection | Joint pain, muscle pain, nerve pain, tiredness, or weakness | [83] | |
HD | Chorea medication | Tetrabenazine | Tablet | Drowsiness, dizziness, insomnia, depression, tiredness, nausea, vomiting | [84] |
Deutetrabenazine | Tablet | Drowsiness, dizziness, insomnia, depression, tiredness, dry mouth, nausea, vomiting | [85] | ||
Antipsychotic medication | Olanzapine | Tablet | Drowsiness, dizziness, headache, dry mouth, weight gain, constipation, stomach upset | [86] | |
Risperidone | Tablet, oral solution | Drowsiness, dizziness, blurred vision, drooling, abdominal pain, dry mouth, nausea, weight gain, tiredness | [87] | ||
Antidepressants (selective serotonin reuptake inhibitors) | Citalopram | Tablet, capsule, oral solution | Nausea, drowsiness, dizziness, blurred vision, loss of appetite, dry mouth, tiredness, sweating, yawning | [88] | |
Fluoxetine | Tablet, capsule, oral solution | Nausea, drowsiness, dizziness, anxiety, insomnia, loss of appetite, dry mouth, tiredness, sweating, yawning | [89] | ||
Sertraline | Tablet, capsule, oral solution | Nausea, drowsiness, dizziness, dry mouth, loss of appetite, diarrhea, upset stomach, insomnia, increased sweating | [90] | ||
Mood stabilizers | Lamotrigine | Tablet | Dizziness, drowsiness, headache, nausea, vomiting, upset stomach, sweating | [90] | |
Carbamazepine | Tablet, capsule, oral suspension | Drowsiness, dizziness, nausea, vomiting, constipation, dry mouth, loss of appetite, skin rash, unsteadiness | [90] |
Disease | Drug | Cellular/Animal Model | Dosage Regimen | Major Drug Target | Significant Outcomes | Reference |
---|---|---|---|---|---|---|
AD | Ibuprofen | Sprague Dawley rats | 2 mg/kg/day intranasally for 6 days | Inactivation of ras homolog gene family member A (RhoA) to suppression of Aβ42 generation |
| [147] |
Curcumin | Streptozotocin-induced AD mice | 5 mg/kg/day intranasally for 20 days | Inhibition of hyperphosphorylation of tau protein, reduction of the Aβ plaque formation, decreasing proinflammatory cytokines, and free radical scavenger. |
| [148] | |
ε-viniferin | In vitro: Murine primary neurons/astrocytes co-culture | 1 μM pretreatment | Disaggregation of amyloid-β peptide. |
| [149] | |
Naproxen | In vivo: AlCl3-induced AD rats | 20 mg/kg/day intraperitoneally for 14 days | Inhibition of caspase-3 expression and also promotes neurogenesis. |
| [150] | |
4′-OH-flurbiprofen-chalcone hybrids | In vitro: BV-2 cell | 0.5, 2.5, and 10.0 μM for 24 h | Inhibition of Aβ1–42 aggregation. |
| [151] | |
PD | Celecoxib | In vitro: SH-SY5Y cells | 5, 15, 20, 25 and 50 μM for 6 h and 24 h | Inhibition of COX-2 enzymatic activity. |
| [152] |
Sodium salicylate | In vivo: Rotenone-treated SD rats | 100 mg/kg/day intraperitoneally for 5 weeks | Inhibition of NF-κB, MAPK, or activator protein-1 (AP-1). |
| [153] | |
Baicalin (5,6,7-Trihydroxyflavone) | α-syn/MPP+ and MPTP-induced PD mice | Pretreated with baicalin (0, 50, 100, 200 mg/kg/day) intragastrically for 7 days followed by a further administration for another 7 days during PD establishment. | Inhibition of NLRP3 inflammasome-mediated inflammation through the Nrf2 pathway. |
| [154] | |
Rubusoside | MPTP-induced PD mice | 150 mg/kg/day intragastric administration from day −3 (i.e., 3 days prior to MPTP administration) to day 24. | Inhibition of JNK/p38 MAPK/NF-κB signaling pathway. |
| [155] | |
Benfotiamine | MPTP-induced PD rats | 100 mg/kg/day (low dose) or 200 mg/kg/day (high dose) orally for 42 days | Targets multiple pathways, including suppression of NF-κB activation, prevents activation of p-38 MAPK and stress-activated kinases (SAPK/JNK), and NADPH-cytochrome c regulation. |
| [156] | |
Linagliptin | Rotenone-induced rat PD rats | 5 mg/kg/day (low dose) or 10 mg/kg/day (high dose) orally for 28 days | DJ-1, Hypoxia-inducible factor 1-alpha (HIF-1α), potentiation in the Sirtuin 1 (SIRT-1)/Nuclear factor erythroid-2-related factor 2 (Nrf-2)/Heme oxygenase-1 (HO-1) pathway. |
| [157] | |
ALS | Nebivolol and donepezil | SOD1G93A mice | Low dose (5 mg/kg/day nebivolol and 3 mg/kg/day donepezil orally) at 10 weeks of age for 70 days High dose: (9 mg/kg/day nebivolol and 6 mg/kg/day donepezil orally) from 63 days of age until the mice could not stand for 30 s | Combination therapy targets multiple key pathways, including inhibition of nuclear factor-κB (NF-kB) nucleus translocation, PI3K-dependent increase in neuronal viability under glutamate excitotoxicity, and upregulation of insulin growth factor-1 (IGF-1) mRNA. |
| [158] |
Masitinib | SOD1G93A rats | 30 mg/kg/day orally starting from day 1 or day 7 post-paralysis for 20 days or until end-stage | Inhibition of tyrosine kinase receptor colony-stimulating factor 1R (CSF-1R). |
| [159] | |
Fingolimod | SOD1G93A mice | 0.1 and 1 mg/kg intraperitoneally 3 times weekly from the onset of symptoms until the end of life | Sphingosine 1-phosphate (S1P) receptor modulator. |
| [160] | |
HD | Azilsartan | 3-NP-induced HD rats | 5 and 10 mg/kg/day orally for 14 days. Animals were euthanized on day 15. | Reduces angiotensin II type 1 receptors and NF-ĸB p65 expression. |
| [161] |
Silyl resveratrol derivatives | 3-NP-induced HD mice | 20 mg/kg was administered intraperitoneally for 2 weeks (avoiding weekends) after disease onset (day 12 post-immunization), and data was collected for 7 weeks. | Like resveratrol, they modulate the AMPK/SIRT1/PGC-1α signaling network. |
| [162] | |
Mangiferin | 3-NP-induced HD rats | 10 and 20 mg/kg orally for 14 days | Inhibit IκB degradation and prevent NF-κB activation. It also acts as a free radical sequester. |
| [163] |
Agent | Phase | Status | Sponsor | Conditions | CT.gov ID |
---|---|---|---|---|---|
Canakinumab | Phase 2 | Active, not recruiting | Novartis Pharmaceuticals | Mild cognitive impairment or mild AD | NCT04795466 |
Celecoxib | Not applicable | Completed | University of California, Los Angeles | AD, dementia | NCT00065169 |
Rofecoxib and Naproxen | Phase 2 Phase 3 | Completed | National Institute on Aging (NIA) | AD | NCT00004845 |
Indomethacin | Phase 3 | Completed | Radboud University Medical Center | AD | NCT00432081 |
Prednisone | Phase 3 | Completed | National Institute on Aging (NIA) | AD | NCT00000178 |
Lovostatin, Ibuprofen | Phase 4 | Completed | National Institute of Mental Health (NIMH) | AD | NCT00046358 |
Rifaximin | Phase 1 Phase 2 | Unknown | Taipei Medical University Shuang Ho Hospital | PD | NCT03958708 |
Ciprofloxacin/Celecoxib | Phase 2 | Completed | NeuroSense Therapeutics Ltd. | ALS | NCT04165850 |
Anakinra | Phase 2 | Unknown | Charite University, Berlin, Germany | ALS | NCT01277315 |
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Giri, P.M.; Banerjee, A.; Ghosal, A.; Layek, B. Neuroinflammation in Neurodegenerative Disorders: Current Knowledge and Therapeutic Implications. Int. J. Mol. Sci. 2024, 25, 3995. https://doi.org/10.3390/ijms25073995
Giri PM, Banerjee A, Ghosal A, Layek B. Neuroinflammation in Neurodegenerative Disorders: Current Knowledge and Therapeutic Implications. International Journal of Molecular Sciences. 2024; 25(7):3995. https://doi.org/10.3390/ijms25073995
Chicago/Turabian StyleGiri, Paras Mani, Anurag Banerjee, Arpita Ghosal, and Buddhadev Layek. 2024. "Neuroinflammation in Neurodegenerative Disorders: Current Knowledge and Therapeutic Implications" International Journal of Molecular Sciences 25, no. 7: 3995. https://doi.org/10.3390/ijms25073995