Alzheimer’s diseases (AD) is a progressive neurodegenerative disease (NDD)NDD associated with cognitive impairment and stands as the first cause of dementia around the world. Clinically, patients show certain symptoms, such as the loss of episodic and semantic memory, that relate to neuronal loss from temporal lobes, particularly at the hippocampus level. As the disease progresses, patients become less self-sufficient, have poorer cognition ability and may require assistance with their daily activities ^[1][29]. AD pathogenesis involves the presence of two components that play a predominant role in its development: Amyloid-β (Aβ) plaques, an abnormal peptide product of amyloid-β precursor protein misfolding and Tau protein neurofibrillary tangles (NFTs). Under normal physiological conditions, amyloid-β precursor protein moderates cell survival, growth, motility, cholesterol binding and metal ion homeostasis, whereas Tau protein promotes cytoskeleton stability and is involved in vesicle transportation ^[2][30]. However, in AD Aβ amyloidogenic fragments oligomerize and form aggregates that eventually accumulate, forming plaques. The formation of these plaques induces the activation of several kinases that, in high concentrations, contribute to Tau hyperphosphorylation, leading to its oligomerization and formation of insoluble NFTs ^[3][31].

Neuroinflammation plays an important role in the pathophysiology of AD as well. Deposits of Aβ plaques and NFTs trigger microglial activation and the local inflammatory response. Consequently, macrophages infiltrate to engulf the plaques; these infiltrations produce pro-inflammatory cytokines, OS and ROS ^[4][32]. In addition, research suggests that Aβ oligomers induce synapse loss and dysfunction, ion channel alterations, impaired calcium homeostasis, increased mitochondrial OS and diminished energy metabolism. NFTs accumulate within neuronal structures, leading to the loss of neuron intercommunication and cytotoxicity, which together enhance neuroinflammation ^[5][33]. With chronicity, neuroinflammation compromises blood–brain barrier (BBB) integrity, which predisposes brain tissue to further damage and inhibits neuroprotection mechanisms ^[6][7][34,35]. Currently, acetyl-cholinesterase inhibitors (AChEIs), such as galantamine, rivastigmine, donepezil and memantine (an antagonist of NMDA), are the available therapies more frequently used for AD; however, none of these options are curative or have shown the ability to slow down or stop disease progression ^[8][36].

Immunization with neural-derived peptides (INDP) also stands as a potential therapy for AD. Glatiramer acetate (GA), an amino acid copolymer, has proven to substantially limit AD evolution. Diverse preclinical studies in murine models have demonstrated that GA administration (varying between nasal, subcutaneous intravenous, alone or combined with vehicle administration) promotes better outcomes ^[9][37]. Initially, in 2005 Frenkel established that nasal administration of GA with a mucosal adjuvant resulted in significant reduction of fibrillar amyloid presence in hippocampal regions that was associated with the reduction of IFN-γ expression in the brain. Studies from 2015 and 2020 demonstrated that weekly subcutaneous GA immunization improved IL-10 levels, Aβ phagocytosis by macrophages, synaptic integrity preservation, astrogliosis restriction and cognitive functions. These results are similar to those obtained by Rentsendorj in 2018, which showed that weekly subcutaneous GA administration promotes the recruitment of peripheral phagocytic cells, induces IL-10 expression and reduces ROS and the pro-inflammatory environment ^{[10][11][12][13]}[38,39,40,41].

The application of INDP as a therapeutic target for AD needs further investigation; however, promising results from several studies over the last years set this therapy as a novel alternative for patients in order to stimulate their own immune system to combat neurodegeneration.

PD is a progressive, neurodegenerative disorder that was first described by James Parkinson in 1817 ^[14][42]. PD is considered as the second most common age-related neurodegenerative pathology, affecting from 5 in 100,000 to more than 35 in 100,000 new cases yearly, with a remarkable increase in its prevalence with age from the sixth to the ninth decades of life, commonly affecting 1% of the population above 60 years ^[15][16][43,44]. The incidence of this disease is higher in males due to estrogen concentrations in females offering profound nerve cell protection ^[17][45]. The cardinal symptoms are associated with motor (bradykinesia, rigidity, resting tremors and postural deformities) and non-motor symptoms. PD has a multifactorial etiology resulting from a combination of environmental, genomic and epigenetic factors, although PARK7, leucine-rich repeat kinase (LRRK2), putative kinase 1 (PINK1), Parkin 2 (PARK2) and PTEN-induced, are some of the well-known genes implicated in the development of the recessive and autosomal dominant forms of the disease. A characteristic hallmark of PD is the loss of dopaminergic neurons from the substantia nigra, pars compacta, in the midbrain ^[18][46]. Another pathologic feature is the presence of Lewy bodies (LB), which are accumulations of intracytoplasmic concentrations of α-synuclein, a protein that under usual physiological conditions, plays a critical role in vesicle fusion, axonal transport and neurotransmitter release, whereas in PD tends to misfold and aggregate, producing cytotoxic effects ^[19][47].

In addition, metabolism of some metal ions, such as copper (Cu) and iron (Fe), have been associated with neurodegenerative conditions, including PD. Cu and Fe are considered redox-active metals, which are essential for optimal brain operations, such as neurotransmitters synthesis, myelin production, synaptic signaling and more, but their high levels produce cell toxicity. However, if their concentrations increase, ROS levels are also going to increase, causing α-synuclein aggregation within LB and lipid peroxidation that lead to DNA destruction and nerve cell degeneration ^[20][48].

Neuroinflammatory events have also been postulated as possible contributors to PD pathogenesis, as it has been confirmed in post-mortem studies that many of the apoptotic nigrostriatal dopaminergic neurons showed high amounts of molecules such as IL-6 and TNFα and apoptosis-related factors such as p55, Fas and caspases 1-2 ^[21][49]. Furthermore, the intermediary molecules resulting from α-Synuclein accumulation trigger innate as well as the adaptive immunity, promoting microglia activation and ROS production, disturbing synaptic function and causing neuronal degeneration and chronic neuroinflammation. Current treatment for PD is mainly symptomatic, including levodopa, dopamine agonists, catechol-O-methyltransferase inhibitors and monoamine oxidase B inhibitors. Nevertheless, these medicines are focused on PD manifestations rather than limiting disease progression ^[22][50]. Likewise, other groups of drugs, such as the AchEIs, memantine and atypical antipsychotics, are focused on treating non-motor symptoms, such as apathy, depression and autonomic dysfunction. Up to the present time, research suggests that INDP should be considered as a treatment for PD due to the beneficial effects that have been reported. Preclinical studies using Cop-1 have demonstrated that after daily administration for 7 days in a murine PD model, mice presented a decrease in midbrain α-Synuclein and microglial marker allograft inflammatory factor 1 (AIF1) levels, an increase in BDNF levels and the animals had an improvement in motor functions, particularly gait and grip strength ^[23][51]. Other studies revealed a significant increase of Th2 T cells in mice immunized with Cop-1, generating a neuroprotective environment, increasing astrocyte-associated glial cell derived neurotrophic factor (GDNF) expression and protecting the nigrostriatal system by modulating microglial responses ^[24][52]. Further studies have followed the path of GA testing in PD models, obtaining promising results after its periodical administration, such as the increase in anti-inflammatory cytokines such as IL-4 and IL-10 and striatal tyrosine hydroxylase expression and inhibition of dopaminergic cells degeneration, which could delay disease progression ^[25][53]. Based on these investigations, INDP remains as a promising therapeutic strategy for PD.

Amyotrophic lateral sclerosis (ALS) is a multifactorial NDD that consists of progressive degeneration and significant death of motor neurons located in the brain and spinal cord ^[26][54]. Recent studies reported an incidence between 0.6 and 3.8 per 100,000 person-years; Europe is the continent with a higher prevalence, ranging from 2.1 to 3.8 per 100,000 person years ^[27][55]. Clinical manifestations include motor and extra-motor symptoms such as muscle weakness, dysarthria, dysphagia and, in severe cases, total movement restriction and respiratory paralysis ^[28][56]. The incidence in America and Europe ranges from one to two cases per 100,000 people yearly. ALS pathogenesis remains partially understood; however, some gene mutations such as superoxide dismutase-1 (SOD1) and TAR DNA-binding protein (TARDBP) appear to be related with the etiology of this condition ^[29][57]. In addition, agriculture jobs, exposure to pesticides and heavy metals, smoking and family history of ALS stand as possible risk factors for developing the disease. It is known that a collection of intracytoplasmic protein inclusions inside motor neurons, mainly constituted by the nuclear TAR DNA-binding protein 43 (TDP-43) and in less proportion by SOD1 aggregation, lead to neuronal dysfunction and even death ^[30][58].

INDP has shown to be a promising therapeutic approach for ALS. In the last decade, several studies in murine models showed that immunization with GA increases life expectancy by protecting motor neurons under protective autoimmunity principles. Anti-inflammatory cytokine expression has been observed in daily GA administration for 2 weeks; thereby, results indicate that this therapy increases the presence of motor neurons in comparison to controls, with a consequent improvement in motor activity ^[31][62]. Novel immunotherapies for ALS are constantly emerging. For instance, in 2019 a study aimed to test the effectiveness of two vaccines against SOD1 misfolding, was based on the principle that immunizing with disease-specific epitopes can induce specific antibody production and a Th2 immune response. Both vaccines demonstrated their capacity to improve the life expectancy of mice with SOD1 mutation by promoting a Th2 immune response and expression of anti-inflammatory cytokines ^[32][63].

INDP, as a therapeutic strategy for ALS, has been successful, and for this reason, stage 1 clinical trials using GA have already been performed, with promising results focused on symptom improvement and patient safety ^[33][64]. Nevertheless, further investigation is required to determine if INDP therapy could increase life expectancy and long-lasting outcomes.

Cerebral ischemia, cerebrovascular ischemia or ischemic stroke (just “stroke” for this rpapesearchr) is a disease caused by the interruption of blood flow or hypoperfusion that leads to brain tissue injury and, if it is not quickly restored, ischemia ^[34][65]. Stroke represents the second cause of sudden death in the world and the most common etiology of neurological disability ^[35][66]. According to estimations, there are 16 million first-time stroke occurrences each year, representing 5.7 million deaths. Approximately 17.8% of the population over 45 years have experienced stroke symptoms and silent cerebral infarction occurs in between 6% and 28% of people, increasing with age. Starting from the age of 65, stroke is the leading cause of disability and patients tend to need long-term care and recovery requirements ^[36][67].

Clinical manifestations depend on the specific brain area affected by the blood flow imbalance; thus, a front-temporal stroke might manifest with motor and language alterations, whereas visual disturbances or blindness are more characteristic of an occipital one ^[37][16]. Stroke survivors commonly present balance difficulties, vision loss, paralysis of the body (specific parts), aphasia, depression and more impairments related to cognitive functions affecting their daily activities ^[38][68].

The etiology includes an embolic event, thrombus formation or even vasospasm, as well as risk factors such as smoking, physical inactivity, obesity, diabetes mellitus, hypertension and others ^[39][69].

In the past, it was known that a stroke could just be an acute isolated event; however, it is now recognized that stroke produces acute and chronic neurodegeneration that can be classified in two adverse events: the initial and secondary injuries. The initial injury refers to the direct result of acute blood flow interruption, which includes neuronal death and severe injury of neurons in the peripheral zone. The secondary injury is the consequence of microglia activation and the initiation of a neuroinflammatory state. After ischemia, M1 macrophages are recruited, with consequent release of pro-inflammatory mediators such as TNFα, IL-1 β, IL-6 and matrix metalloproteases ^[40][70]. In the same way, macrophage infiltration generates ROS and OS which, in addition to metalloprotease production, can directly affect BBB integrity by enhancing endothelial disruption. Together, these reactions generate a cytotoxic and inflammatory environment that, if untreated, will maintain over time and chronically induce cell death and neurodegeneration. Treatment depends on the evolution time and can be classified as intravenous thrombolytics, such as alteplase or tenecteplase, or mechanical thrombolysis, such as endovascular therapy and stent retrievers ^[41][71].

Spinal cord injury (SCI) is a serious and crucial disease that is commonly produced by traumatic mechanisms such as compression, contusion or transection. SCI generates anatomical changes and physiological impairments causing permanent motor and sensory deficits such as spasticity, muscle paralysis, atrophy, gait disorders and pain. Nevertheless, besides muscular, osteoarticular and neuro-psychic systems, this pathology involves many apparatuses of the organism, including the cardiovascular, respiratory, gastrointestinal and genito-urinary systems ^[42][75].

According to epidemiological studies, it is estimated that there are 3.6 to 195.4 cases per million people around the world and the most susceptible group is younger people, from the second to the fifth decade of life. In addition to motor or sensitive symptoms, a particular consequence of SCI is chronic neurodegeneration and cognitive impairment. These aspects are usually left aside for attending more evident clinical manifestations, yet neurodegeneration can considerably affect patients’ life quality and prognosis ^[43][76].

Several studies have shown successful results for INDP in treating SCI in preclinical models. The A91 peptide contains an immunogenic sequence of 87–99 amino acids derived from the myelin basic protein. A91 has proven to induce a Th2 response and the expression of an M2 macrophage phenotype after SCI, increasing the production of anti-inflammatory proteins and neurogenesis in the lesion site. Furthermore, A91 has demonstrated to proportionally reduce the apoptotic mechanisms produced after the injury and plays an important role in inhibiting lipid peroxidation ^[44][81]. In the long term, A91 has shown multiple benefits such as the improvement of motor performance in rat models, which can be explained by a significant increase in IL-4 and TGFβ, molecules that have been found to convey regenerative processes ^[45][46][82,83]. IL-4 alone promotes proliferation of microglial cells, regulates macrophage responses and inhibits the production of proinflammatory cytokines. On the other hand, TGFβ provides restorative mechanisms, has important effects on adult neurogenesis and participates on neural survival ^[47][84].

The GA peptide has also been tested after SCI; however, in contrast with the results obtained in other animal models, GA did not show any beneficial effect ^[48][85]. Although more evidence is clearly needed to be applied on the clinical area, A91 is considered as a promising therapeutic strategy for the acute and chronic stages of SCI.

Traumatic brain injury (TBI) is defined as an alteration in brain functions or other evidence of brain pathology caused by an external force applied to the brain. TBI has many etiologies; nevertheless, falls have been identified as the main cause among children and the elderly population, as well as blast trauma for military members. Other common causes are sport and car accidents involving concussion and head trauma ^[49][86]. Clinical manifestations may depend on the severity, location and mechanism of the traumatic event, ranging from momentaneous or partial lack of consciousness to even coma or death in severe injuries ^[50][87]. It is now recognized that TBI is not just an acute isolated event but a disease with a chronic inflammatory and neurodegenerative component; the damage is classified in two stages. The primary injury consists of the traumatic harm dealt to the brain. The secondary injury is a complex biochemical cascade of events triggered by the primary injury ^[51][88].

Neuroinflammation is an essential component for secondary injury and chronic degeneration. Inflammatory-related injury begins after initial neuronal and axonal injury, with the subsequent liberation of damage-associated molecular patterns that activate cell networks, inducing inflammatory gene expression for immune response regulation. Neutrophilic infiltration and the microglial response are triggered in parallel with pro-inflammatory molecules such as TGF1-β, IL-6 and IL 8 production ^[52][89]. Recent studies suggest that neuroinflammation enhances glutamate receptor production as well as GABA receptors internalization, which promotes neuronal overstimulation and toxicity. Moreover, cytotoxic and inflammatory environments promote ROS and OS production, which leads to metabolic imbalance, endothelial dysfunction and BBB leakage ^[53][90]. Treatment for TBI is limited and includes supportive measures to avoid auditory, visual and physical stress, as well as some interventional therapies such as hyperosmolar therapy, targeting intracranial pressure and hyperbaric oxygen, which has shown apoptosis inhibition, inflammation suppression, BBB protection and angiogenesis/neurogenesis promotion ^[54][91].