Hypothesis: apo‐lactoferrin–Galantamine Proteo‐alkaloid Conjugate for Alzheimer's disease Intervention

Abstract

Alzheimer's disease (AD) is known to be caused by the accumulation of deformed beta amyloid and hyperphosphorylated tau proteins resulting into formation and aggregation of senile plaques and neurofibrillary tangles in the brain. Additionally, AD is associated with the accumulation of iron or metal ions in the brain which causes oxidative stress. Galantamine (Gal) is one of the therapeutic agents that has been approved for the treatment of AD, but still saddled with numerous side effects and could not address the issue of iron accumulation in the brain. The use of metal chelators to address the iron accumulation has not been successful due to toxicity and inability to address the aggregation of the plaques. We therefore hypothesize a combinatorial antioxidant–metal–chelator approach by formulating a single dosage form that has the ability to prevent the formation of free radicals, plaques and accumulation of iron in the brain. This can be achieved by conjugating Gal with apo‐lactoferrin (ApoLf), a natural compound that has high binding affinity for iron, to form an apo‐lactoferrin–galantamine proteo‐alkaloid conjugate (ApoLf–Gal) as a single dosage form for AD management. The conjugation is achieved through self‐assembly of ApoLf which results in encapsulation of Gal. ApoLf changes its conformational structure in the presence of iron; therefore, ApoLf–Gal is proposed to deliver Gal and pick up excess iron when in contact with iron. This strategy has the potential to proffer a dual neuroprotection and neurotherapeutic interventions for the management of AD.

Rusty Microglia: Trainers of Innate Immunity in Alzheimer's Disease

“…On the other hand, a recent study demonstrated that iron and ROS can inhibit α7nAChRs signaling, likely disrupting tolerized immunity (209, 210). Interestingly, conjugation of an AChEI, such as galantamine, with the natural iron chelator, lactoferrin, was recently proposed as an AD therapy (211).…”

Clinical impact of high-profile animal-based research reported in the UK national pressClinical impact of high-profile animal-based research reported in the UK national press

“… 46 Other caveats are still being reported: galanthamine treatment is ‘still saddled with numerous side effects’. 47 …”

“…46 Other caveats are still being reported: galanthamine treatment is 'still saddled with numerous side effects'. 47 In summary, there was substantial, significant weight of evidence of the role and ACh in AD prior to the 1995 rat experiments; much of this was human specific and much of this was acknowledged by the authors themselves. Drugs targeting this pathway were already in clinical development, and so it cannot be claimed that galanthamine development depended on animal research-and certainly not on this particular research-due to the extensive human data relating to it, which go back hundreds of years, and which include detailed pharmacodynamic and Open access pharmacokinetic data preceding 1995.…”

A Review on Pharmacological Potential of Galantamine

“…27 Passive avoidance test on NMBlesioned mice Improved performance. 28 Scopolamine -induced passive avoidance test GAL injection significantly reduces scopolamine induced learning and memory deficits, as well as inhibited scopolamine induced passive avoidance. 29 Investigation of ability of GAL to allosterically modulate nAChR using young and older rabbits Significant up-regulation of nicotinic sites; showed signs of tolerance to GAL and attenuation receptor up regulation.…”