Article type: Literature Review
Article title: Galantamine-Memantine Combination in the Treatment of Parkinson’s Disease Dementia
Journal: Brain Science
Year: 2024
Authors: Emma D. Frost, Swanny X. Shi, Vishnu V. Byroju, Jamir Pitton Rissardo, Jack Donlon, Nicholas Vigilante, Briana P. Murray, Ian M. Walker, Andrew McGarry, Thomas N. Ferraro, Khalid A. Hanafy, Valentina Echeverria, Ludmil Mitrev, Mitchel A. Kling, Balaji Krishnaiah, David B. Lovejoy, Shafiqur Rahman, Trevor W. Stone, and Maju Mathew Koola
E-mail: jamirrissardo@gmail.com
ABSTRACT
Parkinson’s disease (PD) is a progressive neurodegenerative disorder that affects over 1% of population over age 60. It is defined by motor and nonmotor symptoms including a spectrum of cognitive impairments known as Parkinson’s disease dementia (PDD). Currently, the only US Food and Drug Administration-approved treatment for PDD is rivastigmine, which inhibits acetylcholinesterase and butyrylcholinesterase increasing the level of acetylcholine in the brain. Due to its limited efficacy and side effect profile, rivastigmine is often not prescribed, leaving patients with no treatment options. PD has several derangements in neurotransmitter pathways (dopaminergic neurons in the nigrostriatal pathway, kynurenine pathway (KP), acetylcholine, α7 nicotinic receptor, and N-methyl-D-aspartate (NMDA) receptors) and rivastigmine is only partially effective as it only targets one pathway. Kynurenic acid (KYNA), a metabolite of tryptophan metabolism, affects the pathophysiology of PDD in multiple ways. Both galantamine (α7 nicotinic receptor) and memantine (antagonist of the NMDA subtype of the glutamate receptor) are KYNA modulators. When used in combination, they target multiple pathways. While randomized controlled trials (RCTs) with each drug alone for PD have failed, the combination of galantamine and memantine has demonstrated a synergistic effect on cognitive enhancement in animal models. It has therapeutic potential that has not been adequately assessed, warranting future randomized controlled trials. In this review, we summarize the KYNA-centric model for PD pathophysiology and discuss how this treatment combination is promising in improving cognitive function in patients with PDD through its action on KYNA.
Keywords: cognition; drug combination; galantamine; kynurenic acid; memantine; N-acetylcysteine; neuropharmacology; Parkinson’s disease dementia; Parkinson’s disease treatment
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DOI
Citation
Frost ED, Shi SX, Byroju VV, Rissardo JP, Donlon J, Vigilante N, et al. Galantamine-memantine combination in the treatment of Parkinson’s disease dementia. Brain Sci 2024;14:1163.
Figure 1. Kynurenine pathway. An abbreviated depiction of the kynurenine pathway showing the major steps.
Figure 2. Overview of the kynurenine pathway in the brain and its effects. Depiction of the differential expression of the KP in cells of the central nervous system. Astrocytes lack the full complement of KP enzymes, hence KP activation in astrocytes terminates in the production of neuroprotective KYNA. However, as microglia fully express KP enzymes, KP activation in microglia can result in the production of neurotoxic metabolites 3-HK and QUIN. KP = Kynurenine Pathway; TRP = Tryptophan; KYNA = Kynurenic Acid; IDO = Indoleamine 2,3-dioxygenase; TDO = Tryptophan-2,3-dioxygenase; QUIN = Quinolinic Acid; 3-HAA = 3 Hydroxyanthranilic Acid; 3-HK = 3-hydroxykynurenine; KMO = Kynurenin-3-monooxygenase; KYN = Kynurenine.
Figure 3. Kynurenine pathway-centric pathophysiology model. Depiction of some of the receptors, pathways, and processes affected by increased levels of major kynurenine pathway metabolites KYN, KYNA, 3-HK, and QUIN after pathway activation. AhR = aryl hydrocarbon receptor; α7nAChR = Alpha7 nicotinic receptor; BCL-2 = B-cell Lymphoma 2; GABA = γ-aminobutyric acid; KYN = Kynurenine; KYNA = Kynurenic Acid; NMDA = N-methyl-D-aspartate; QUIN = Quinolinic Acid; 3-HK = 3-hydroxykynurenine. ↑, increased process; ↓, decreased process.
Figure 4. Magic bullet versus shotgun approach. The magic bullet approach has long been thought to be the answer to treating complex medical conditions. Pharmaceutical companies hoped that they would be able to develop a single drug to treat many conditions. However, this has failed countless times. We argue that the shotgun approach is more effective. Using multiple drugs (shotgun approach) to target multiple pathways implicated in a disease is likely to a more effective treatment approach.
Table 1. Meta-analyses of randomized controlled trials in schizophrenia: potential medications in Parkinson’s disease (PD).