Review on Nose-To-Brain Drug Delivery

Neurological diseases are the leading cause of disability worldwide, adding the burden on healthcare^(1). Brain medicine delivery is challenging due to the Blood Brain hedge (BBB), the complexity of the brain, and safety and toxin enterprises. Nose- to- brain medicine delivery has surfaced as a novel,non-invasive route with advantages over systemic medicine administration similar as Elusion of systemic toxin, better side effect profile,non-invasiveness, short quiescence, and increased Central Nervous System (CNS) bioavailability. Nose- to- brain medicine delivery bypasses the BBB through neural connections among the olfactory epithelium, olfactory bulb, trigeminal whim-whams, and the brain ^(2).

Define: Nose to brain drug delivery system is a novel invasive technique that allows direct transportation of therapeutic drugs from the nasal cavity to the brain through the olfactory and trigeminal neural pathways by passing the blood-brain barrier ^(3). This system enhance drug absorption in the brain, provides faster onset of action and minimizes systemic side effect ^(4).

Alzheimer’s Disease: Number of patients suffering from neurodegenerative diseases and other central nervous system (CNS) disorders has shown a continuous increase that is associated with the aging population during the last decade ^(5). Alzheimer’s disease (AD), Parkinson’s disease, schizophrenia, migraine, malignant glioma, vestibular schwannoma, meningitis, and multiple sclerosis are representative CNS-related diseases ^(6).

Neurofibrillary tangles and plaques containing β-amyloid is what biologically characterizes Alzheimer’s disease (AD) ^(7). The classic presentation of AD, a hereditary and sporadic neurodegenerative disease, is amnesty” cognitive impairment; its less prevalent variations, on the other hand, induce non-amnestic cognitive impairment ^(8). Although AD is a prevalent cause of cognitive impairment that develops in midlife and late life, other neurodegenerative and cerebrovascular disorders can alter its clinical impact ^(9). Between 60 and 70 percent of all occurrences of cognitive impairment in the senior population are caused by Alzheimer’s disease (AD), a progressive neurodegenerative illness ^(10).

It is typified by a slow deterioration in behavioural, cognitive, and memory abilities that eventually results in total dependence ^(11). It is estimated that 2.3 million persons in the US have Alzheimer's disease (with a range of 1.09 to 4.8 million^. The number of cases increases every five years after age 60. While a variety of progressive and fatal neurological conditions were known at that time, including senile dementia, the early age four years later1.

SYMPTOMS:

Alzheimer’s disease causes symptoms that get worse over time, and they are different from the normal changes that happen as people get older ^(12).

These symptoms often start with memory problems:

• Memory Loss: Forgetting new information, asking the same questions again, and losing things are early signs ^(13).
• Cognitive Decline: Trouble with solving problems, handling money, or doing daily tasks that used to be simple ^(14).
• Disorientation: Getting confused about time, dates, or places, even in places that are very familiar.
• Language Problems: Difficulty finding the right words, keeping up in conversations, or naming objects ^(15).

CAUSES & RISK FACTORS OF AD:

Causes & Risk Factors of AD

PATHOPHYSIOLOGY:                                                                                                       

Fig: Pathophysiology Of AD

ALZHEIMER’S DISEASE (AD) PATHOGENESIS:

The pathogenesis of Alzheimer’s disease involves two major hypotheses that explain how neuronal damage and cognitive decline occur ^(16):

1. Amyloid Cascade Hypothesis:

This is one of the most widely accepted explanations for Alzheimer’s disease. According to this hypothesis ^(17):

Intracellular deposition of neurofibrillary tangles (NFT) and extracellular deposition of amyloid-beta (Aβ) plaques Lead to a series of damaging cellular events.

2.The Cholinergic Hypothesis:

According to this theory, the primary cause of Alzheimer’s disease is a lack of the neurotransmitter acetylcholine (Ach), which is essential for memory and learning ^(18).

It includes:

Decrease in the enzyme that breaks down acetylcholine, acetylcholinesterase (unbalanced enzyme activity impacts signalling) ^(19).

Acetylcholine neurotransmitter levels drop as a result, which leads to:  Impairment of the transmission of nerve impulses, these abnormal protein accumulations cause, Disruption of calcium (Ca²?) Homeostasis, Overproduction of free radicals, leading to oxidative stress ^(20).

WHY DIAGNOSIS IS IMPORTANT.

Early Interventions: An early diagnosis gives you more time to begin treatments, seek support, and plan for future care. Excluding Other Causes: Many illnesses can cause memory and thinking issues, and a comprehensive diagnosis can help identify and cure these conditions if they exist.

TREATMENT:                                      

Fig. Treatment

Approved Symptomatic Treatments for Alzheimer’s Disease Current authorized symptomatic therapies include: Donepezil (Ache) Galantamine (Ache) Rivastigmine (Ache). Memantine (an NMDA receptor antagonist). Donepezil + Memantine combination

Combination with Disease Modifying Therapies Drug Targets and Agents. 1. The amyloid cascade: BACE Inhibitors A β monoclonal antibody. Aβ vaccination 2. Tau Aggregate: Tau active immunization. Tau passive immunization. 3. Other targets: Tyrosine kinase inhibitors RAGE inhibitors Anti-inflammatory agents ^(21). Angiotensin II receptor antagonist Sc/Abl kinase family inhibitor GM-CSF Vitamin B3 11β-hydroxysteroid dehydrogenase inhibitor. Sigma-1 chaperone agonist Deep Brain Stimulation Repetitive transcranial magnetic stimulation (rTMS). Sigma-2 receptor ligand. PPARγ agonist A microtubule stabilizer --- Combination of Symptomatic Therapies Agents: 5-HT receptor antagonist, MAO-B inhibitors, Anticonvulsant and serotonin receptor agonists ^(22). Glutamate Neurotransmission Modulator Symptom Targets: Cognition Agitation Aggression Non-convulsive seizures ^(23).

RECENT ADVICES:

Fig: Recent Advices in Alzheimer’s Disease

Disease-modifying Therapies Monoclonal Antibodies: FDA-approved medications such as lecanemab and aducanumab target and eliminate amyloid-beta in the brain, halting disease development . Future Targets: Other antibodies targeting amyloid-beta and the tau protein, both of which are associated with Alzheimer’s disease, are being studied ^(24).

CHALLENGES AND FUTURE DIRECTION: 

Challenges and Future Directions. Blood-Brain Barrier (BBB) Penetration: One key problem is effectively getting medications over the BBB to the brain^. Amyloid-Associated Imaging Abnormalities (ARIAs) ⁽²⁵⁾ Monoclonal antibody therapies have been linked to adverse effects such as cerebral edema and microhaemorrhages. need for a cure: Current disease-modifying medications assist control the condition, but they do not cure Alzheimer’s or repair damaged neurons ^(26).

NEW DIRECTION OF ALZHEIMER’S DISEASE:

FUTURE STRATEGY:

Fig: Future Strategies of Alzheimer’s Disease