Neurological therapeutics is the branch of medicine dedicated to the development and provision of treatment for individuals suffering from neurological disorders or injuries such as stroke, epilepsy, and Alzheimer's disease. These conditions all result from damage or dysfunction of the nervous system, one of the leading contributors to disease worldwide. Nearly ten million deaths due to neurological disorders were seen in 2019, with 6.5 million deaths internationally recorded from stroke sufferers alone. With an ageing population, there is now a rising proportion of people who suffer from neurological diseases. Ultimately, this increase results in greater human and economic burden due to the large workforce required to research and administer treatment, as well as the cost of supplies and clinical trials. Careful analysis of these diseases is pivotal in the development of effective treatments for neurological disorders and delay of their onset.
Issues with Current Therapeutic Approaches
Treatments for neurodegenerative disease such as Alzheimer’s and Parkinson’s tend to be medication which target specific symptoms such as pain and mobility difficulties. Neuromuscular disorders affect motor and sensory nerves responsible for connecting the brain and spinal cord to the rest of the body. Treatment plans will usually also include rehabilitation with physical, occupational and speech therapy.
Causes of epilepsy are largely a mystery and it is thought to be linked to brain injury, genetics, strokes or tumours. The first line of treatment for epilepsy is antiepileptic medication which prevents recurrence of seizures, but unfortunately, 20% of all epilepsy patients experience seizures which do not respond to treatment. If the patient is medically resistant, they may be treated at a specialised epilepsy centre using treatment options such as surgery, vagal nerve stimulation and diet therapy.
In neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease, treatments primarily target the management of symptoms rather than addressing the underlying cause of neurodegeneration. Despite efforts to delay disease progression, patients will inevitably experience cognitive decline which will continue to impair their functional activities, highlighting the need for improved forms of neuromodulation. Similarly, due to the lack of knowledge about the origination of epilepsy, the treatment administered is ineffective against the underlying cause of epilepsy in the patient.
Treatment for strokes depends on the specific type: ischaemic stroke (oxygen supply to the brain is disrupted), focus on restoring normal blood through drug therapy or sometimes a catheter insertion into the blocked brain artery is required to remove the blockage. Haemorrhagic stroke (bleeding inside or outside of the brain) is contrastingly treated by locating the source of a bleed and controlling it. This sometimes involves surgery and treatment in intensive care including the use of anticoagulants to eliminate any blood clots in the brain’s venous drainage system.
It is important to consider that in stroke management, emergency treatment may not always be sufficient to prevent the long-term effects of a stroke. A multifaceted treatment plan, consisting of medication, rehabilitation and lifestyle intervention should be utilised to optimise outcomes for stroke sufferers. Surgery involved in the treatment of haemorrhage stroke carries many risks and may not be a suitable care approach for all patients. This suggests that there is a need to have more targeted and personalised approaches to ensure that the appropriate care is provided for the patient.
An important factor in all therapeutic care is patients’ socioeconomic backgrounds and accessibility to effective neurological services. Limitations in this aspect fuel disparities in healthcare. Patients who experience socioeconomic barriers to healthcare may seek professional healthcare advice at a later stage or choose to refrain from proceeding with certain treatment options, which affects their neurological prognosis.
Advancements in Neurological Therapeutics
Numerous clinical trials and extensive research are being carried out in order to tackle these hurdles in therapeutics. New technologies include the use of nanotechnology for efficient drug delivery, and gene editing which aims to assuage and potentially cure brain disorders. Technology can also be used to better understand the underlying causes of neurological diseases.
Nanotechnology
One obstacle in therapeutic drug delivery is the blood-brain barrier, a highly selective barrier surrounding the brain which allows the passage of necessary nutrients such as glucose and amino acids to the brain, while preventing the diffusion of large hydrophilic molecules such as prescribed drugs into the central nervous system. To overcome this, non-invasive procedures such as nanotechnological drug delivery are being developed to enable effective delivery of medication. The small size, surface charge and lipophilic nature of nanoparticles enable them to effectively be absorbed into the brain endothelial cells and desorbed into the bloodstream where they can release encapsulated drugs on the blood brain barrier surface able to diffuse through the parenchyma (essential functional tissue) of the brain. The roles and structures of nanoparticles vary, with dendrimers, liposomes, micelles, PNPs and solid-lipid nanoparticles being a few common examples.
Recognised for their adaptability when it comes to drug delivery, dendrimers consist of an interior core with branching dendrites and a peripheral shell. The use of dendrimers has been effective in targeted therapeutics, however, the possibility that they may trigger unwanted immune responses such as inflammation or autoimmunity must be considered as this can hinder treatment.
Liposomes are small hydrophilic colloidal vesicles with a centre consisting of one or more lipid bilayers. In this way they are similar to the cell membrane and can be applied in the treatment of brain cancer as they are able to cross the blood brain barrier and deliver anti-cancer drugs directly to the target site. Ways in which liposome technology can be improved are under investigation and currently include coating with other molecules, using a glycoprotein target receptor and incorporating a glucose-vitamin C complex.
Micelles, which consist of an inner and outer hydrophobic component, are particularly useful in delivering drugs which are not very water soluble as they maintain the physical and chemical stability of the drug and sustain their release to the desired site.
Protein nanoparticles (PNPs) deliver lipophilic drugs to the target site by encapsulating or chemically attaching the drug to its surface. A lab study was performed to show the use of PNPs for the delivery of curcumin for treatment of Alzheimer’s disease reduced inflammation, plaque formation and oxidative stress levels were observed in the duration of use.
Colloidal mixtures containing lipids such as triglycerides and fatty acids make up solid-lipid particles (SLNs). The key feature of these nanoparticles is their ability to turn into a solid when spread through a solution and cooled. SLNs pique interest in neurological therapeutic development as they are physically stable, have low cytotoxicity and protect drugs from alteration, making them suitable for use in drug delivery systems. They are able to transport hydrophilic and lipophilic drugs better than PNPs and immobilise the drug within its encapsulation, protecting it before it reaches the site of administration.
Gene Editing
An effective therapeutic strategy for many neurological disorders is gene editing. This involves recognition of the faulty gene responsible for the disorder and the use of a high precision tool, called CRISPR to disrupt the gene sequence. The CRISPR operates using short RNA sequences (guide RNAs) to identify affected alleles. The CRISPR/Cas (Cas referring to nucleases attached to the CRISPR to cleave DNA) system is directed to the target site by guide RNA and initiates a repair mechanism to correct point or frameshift mutations. Gene therapy is especially useful for neurodegenerative disorders and the CRISPR-Cas9 protein has been used to develop models of such diseases and target genes to lessen abnormalities.
Gene editing can be useful in stem-cell intervention which may be used in the treatment of neuromuscular disorders. The process entails harvesting stem-cells from adipose tissues, then editing and inserting the gene into the intrathecal space (the region between the spinal cord and the strong, thin membranes that envelop and shield it).
Limited efficiency and precision in gene-editing pose great challenges. Currently, the CRISPR-Cas complex corrects less than 10% of faulty alleles. Off-target effects can occur when CRISPR/Cas systems act non-specifically on non-targeted genome sites and can lead to adverse outcomes. Computational models can be used to search for potential off-target sites and calculate the probability of off-target editing, but even so further improving the specificity of CRISPR/Cas systems will be essential in order to minimise unwanted gene mutations.
Improvements in Research
Improvements in research are necessary to prevent misdiagnosis of neurological disorders and develop more efficacious treatment. The use of neuroimaging and machine learning, including using algorithms to analyse and quantify brain function, is shown to be promising for the early diagnosis of Alzheimer’s disease. The use of machine learning algorithms for learning complex patterns in the progression of a mild cognitive impairment to Alzheimer’s disease is a powerful tool in therapeutic research.
Furthermore, the use of neuroimaging such as PET and MRI scanning is key in obtaining comprehensive neurological data for treatment development. There are various other neuroimaging techniques, each with their own limitations and advantages, and these must be considered and developed upon in order to provide higher standards of care in the neurological field.
Precision medicine
Precision medicine involves tailoring treatment strategies to individual patients by considering factors such as their clinical phenotype, environment (e.g. lifestyle and diet) and a molecular analysis. By doing a molecular analysis, healthcare professionals are able to gain a deeper understanding of the cause of disease and its functional consequences. Combining this information with knowledge of the patient’s lifestyle and clinical features (e.g. height, weight, blood pressure) enables a more well-rounded understanding of the patient’s condition to be achieved. Using such data, a more personalised approach can be pursued in the hopes of achieving better prognostic results.
In conclusion, progress in gene editing, nanotechnology, improved research techniques, and precision medicine will propel a large advancement in neurological therapeutics in the future. These innovative methods have the potential to provide extremely effective and individualised therapy, welcoming new development in neurological care and enhancing patient outcomes globally.