Patent Application
20220273804
The present invention is a composition of buckminsterfullerene with gamma amino butyric acid (GABA) and levodopa (L-dopa) or dopamine (DOPA) pendant groups that can function as a dual neurotransmitter, and methods of use to prevent or to treat degenerative neural disease and loss of motor neuron control that is associated with synaptic damage or neural cell death in susceptible cells. Delivery methods include ingestion, inhalation, or injection when used as a medicament or as a food supplement to maintain or re-establish benign healthy neural cellular homeostasis.
Parkinson's disease (PD) is a movement disorder driven by the loss of dopamine producing neurons in the substantia nigra (SN) region of the human brain. PD is characterized by difficulty in initiating movement, muscle rigidity, muscle tremors, and an inability to maintain a stable posture. The motor dysfunctions represent the major clinical features of this disease. Non-motor symptoms such as sleep disturbances, dementia and depression may also be present. Motor disturbances are primarily produced by the degeneration of dopamine neurons in the SN, as well as the projections from this region to the striatum. Additional regions of neurons may also be affected in the disease. One short term treatment strategy was based on prescribing dopamine neurotransmitter agonists. However, it was found that even when administered in combination with dietary antioxidants, dopamine promotors and dopamine itself can be ineffective or even produce negative effects after long-term administration.
Decreased levels of total glutathione (GSH) and oxidized glutathione (GSSG) with 40% to 50% deficit were found in the substantia nigra region of the autopsied brains from deceased patients with PD by Perry and colleagues in the 1980's. Later, a similar loss of antioxidant GSH in the substantia nigra was found in Incidental Lewy body disease. Lewy body disease is thought to be an early form of PD. In these cases, oxidative damage to lipids, protein, and DNA in the nigra of PD patients occurs. Past clinical trials attempting to treat PD have used antioxidants targeted to substitute for GSH, but these substances have shown little benefit, likely because of low bioavailability to the brain.
Identification of the oxidative properties of dopamine implicated it as one potential source of oxidative stress in PD when it is present under oxidative conditions. The discovery of PD-causing mutations causing alpha-synuclein aggregation in the Incidental Lewy body pathology of PD leading to neurodegeneration was later clarified by manipulation of both dopamine levels and α-synuclein expression in aged mice. It was then found that only the combination of these 2 factors caused progressive neurodegeneration of the SN region of the brain and an associated motor deficit.
Alpha synuclein in fibril form is a 14 kilo-Dalton protein. The neurodegenerative disorders associated with alpha-synuclein plaques are collectively known as synucleinopathies. The major components of intraneuronal inclusions containing alpha-synuclein plaques are termed Lewy bodies. It is now well understood that the key symptoms of PD and Lewy body disease is the aggregation of alpha-synuclein protein fibrils into pathogenic alpha-synuclein plaques. Such toxic plaques act as a catalyst to agglomerate and recruit healthy independent alpha-synuclein fibrils into greater numbers of oligomeric toxic plaques. The alpha-synuclein plaques and other types of oligomeric plaques such as those generated by Alzheimer's disease or perhaps even those oligomeric particles that are implicated in amyotrophic lateral sclerosis can be considered a type of prion, although these plaques may be better termed idiopathic or systemic prions and are likely not infectious between individuals. However, toxic oligomeric plaques are quite capable of migrating along the neurons to affect the neural structures in the gut, the vagus nerve, and anywhere that neurotransmitters such as dopamine can be exchanged between synapses of different neural cells.
Genetic point mutations were found to cause autosomal forms of PD by pathogenic disruption of the amino acids in the hydrophobic N-terminal domain of alpha-synuclein to cause nucleation and aggregation into β-sheet-rich oligomeric plaques. Under some oxidative conditions, the oligomer attaches to the neurotransmitter dopamine and can migrate from neuron to neuron and thereby modify alpha-synuclein aggregation in the SN, resulting in greater abundance of alpha-synuclein oligomers and dopamine-induced plaques. Furthermore, it was found that by disrupting the dopamine-α-synuclein interaction under these conditions, dopaminergic neuronal degeneration was reversed. Equally important and extensive evidence from cultured cells and cell-free solution testing indicates that the neurotransmitter dopamine may, under reducing conditions, reverse or inhibit the aggregation of alpha-synuclein. At present, L-dopa, a dietary supplement that metabolizes into dopamine neurotransmitter, is the most widely used and most effective therapy for Parkinson's disease (PD).
Elevating dopamine levels under either oxidizing or reducing conditions either increased or reduced the number of cells containing insoluble and large intracellular alpha-synuclein plaques. This demonstrated that the interaction of dopamine and alpha-synuclein is noncovalent and reversible, and it also demonstrated that reduction-oxidation (REDOX) conditions reversed the conditions associated with PD. It is historically and medically significant to understand that oxidized dopamine promotes the formation of alpha-synuclein plaques that become neurotoxic in large concentrations. This pathology is caused by disrupting cytoskeletal organization in neural lipid membranes that reduce synaptic terminal membrane permeability and affects neural signaling by blocking calcium ion transport.
In more detail, it is now clear that healthy individual alpha-synuclein fibrils in neurons bond with the inner (cytosolic) leaflets of the presynaptic membrane leaflet to induce a concentration dependent stabilization of docked and double-anchored synaptic vesicles. Neurodegenerative oxidative and free radical damage forms cross-links within and thickens the overall lipid composition of the cellular membranes. This chemical change allows alpha-synuclein to bond to outer presynaptic membranes and disrupts the correct morphology and conformation of alpha-synuclein, encouraging the formation of plaques. The movement of toxic plaques to the inner presynaptic membranes then causes dysfunctional disruption of synaptic vesicle membrane transport.
On a related topic, glutathione (GSH) is the most abundant small molecule, non-protein thiol in cells that acts as a reducing agent. It consists of a tripeptide of glutamate, cysteine, and glycine. Within neurons, GSH is found in greatest abundance at nerve endings. It is now well understood that GSH in the neural synapse serves as a REDOX regulator that functions to control and maintain intracellular REDOX. Moreover, the absence of reductive GSH in the substantia nigra region of the brain leads to dysregulated conditions that promote neurotoxic alpha-synuclein plaque formation. The degeneration of dopaminergic neurons in the substantia nigra during PD is therefore directly related to GSH depletion that leads to elevated levels of nitric oxide and peroxynitrite oxidants, leading to oxidative stress damage. This damage inhibits the REDOX complexes of the electron transport chain, causes a drop in the proton motive force, and reduces ATP production to further magnify the REDOX dysfunction by causing mitochondria to significantly reduce GABA (GSH) synthesis. The further loss of GSH increases oxidative and free radical damage to surrounding cellular lipids and increasingly creates those toxic conditions leading to neurodegeneration.
Given these understandings of the etiology and neuronal disease characteristics associated with the progression of PD, designs of materials or compositions able to decelerate or alleviate PD and related motor neuron disease progression is now better focused, and the targets of oxidative stress and plaque formation have achieved great importance. In particular, the anti-aggregation effect of fullerenols, previously demonstrated for various forms of amyloid proteins, was also observed to be somewhat effective for the reduction of alpha-synuclein insoluble protein aggregates. The limited fullerenol neuroprotective activity was not affected by the number of carbon atoms in the fullerenol compounds, so that polyhydroxylated C60 or C70 was able to act equally well. While fullerenols might be a promising tool for drug development to treat PD, these materials are also understood to be insufficiently targeted to the specific regions of neuronal dysfunction, such as the SN region of the PD brain, and do not have an established or significant ability to cure or prevent PD.
The consensus among scientists and medical practitioners is that oxidative stress plays a major role in the development of neural cellular metabolic disease. Some of the current therapeutic strategies have put emphasis on the design of multiple functional properties into molecules or particles that enable them to target multiple enzymes or receptors, allowing them all to operate at the same time to avoid or correct the dysfunctions leading to disease states. Of these, several natural antioxidants have been known for their ability to trap and scavenge free radical species and reactive oxygen species (ROS) such as hydroxyl and nitrate free radicals. ROS are associated with causing damage to essential cellular components, and neurodegenerative diseases.
While there is great promise in the widely known beneficial neuroprotective functions of gamma-aminobutyric acid (GABA) in the brain, there are no known strategies to enhance its poor oral bioavailability to deliver this substance to the substantia nigra portion of the human brain. This is because it is widely believed that one of the precursor glutamine or glutamine amino acids already penetrate the blood-brain barrier, and therefore the methionine cycle will work to generate GABA endogenously and locally. However, it is also verified that the endogenous production of certain substances like glutathione has failed locally in the Parkinson's brain. It happens that glutathione is also involved in the methionine cycle. Thus, the medical evidence for sufficient endogenous GABA production in all brain tissues remains an assumption or a hypothesis not yet proven or disproven by conclusion. This type of investigation is important because GABA is the principal inhibitory neurotransmitter in the mammalian central nervous system. Dysregulation of GABA is already implicated in many neurological disorders, such as in Alzheimer's disease, epilepsy, panic disorder, and anxiety.
GABA is what is called a zwitterion. In this nature of GABA, the amine and the carboxylic acid groups on this molecule are both protonated and deprotonated, respectively, at physiological pH. Endogenously produced GABA is a neurotransmitter that has outstanding benefits, including reducing blood pressure, enhancing long-term memory, and improving diabetes by controlling the secretion of insulin. However, GABA is easily broken down by neural enzymes, especially as released by astrocytes. This technological hurdle may help to explain why a possible beneficial effect of GABA into the brain to treat Parkinson's disease has never been studied or seriously practiced in medical neuroscience.
Many proposed treatments or compositions in clinical trials have proven insufficiently bioavailable, being poorly soluble in water or being unable to pass cellular membranes. Typical drug loading of about 10% is achieved for nanoparticles of a narrow size distribution around an average size of about 100 nanometers when encapsulated in water soluble polymer micelles. While this method suggests complete dispersibility of drug substances, the dispersion bonding is often substantially irreversible, and may lead to significant masking of the therapeutic agent, along with poor targeting to the appropriate molecular receptors and affected structural regions of neural cells. The dual bioavailability and specific targeting problems remain significant obstacles to any significant commercial and medical success of multifunctional prophylactic protective and therapeutic neurological compositions for alpha-synuclein or dopamine dominated neural dysfunction and neurological disease.
Dopamine agonists are state of the art medications based on a derivative of dopamine that have been medically proven to stimulate the parts of the human brain influenced by dopamine. The neurons of the brain, especially in the substantia nigra where motor control is interfaced with control signals propagating into and from the brain stem, can accept these exogenous, artificial, and introduced dopamine substitutes. The neurons are then able to perform and function as if accepting the endogenous dopamine that these neurons need but have not been able to receive in sufficient quantity over the early stages of the neurological disease. In general, dopamine agonists are not as potent as carbidopa or levodopa and may be less likely to cause dyskinesias. However, a better solution is not commercialized yet, and most people who take levodopa develop motor control problems within 5 to 10 years after starting their dopamine agonist medicine. These complications are unpredictable swings in muscular position control between doses and uncontrollable jerking or twitching (dyskinesias). Dyskinesia can become so intense that that it is as disabling as some of the problems caused by the neurological disease. In the longest study done, people who started treatment with a dopamine agonist had just as many problems with motor fluctuations at 14 years as people who started treatment with levodopa, indicating a failure to prevent oxidative damage at the post synaptic bouton, a failure to protect neurons from cell death, and a failure to prevent the accumulation of toxic brain protein oligomers such as alpha-synuclein plaques that are a cause of neural cell death. The study of Olanow (2013) published that those observed factors most predictive of developing dyskinesia from L-dopa and agonists of dopamine in combination with L-dopa. These predictive results are ranked order from most to least, being: (1) young age at onset, (2) higher L-dopa dose, (3) low body weight, (3) North American geographic region, (4) The L-dopa with carbidopa and entacapone (two agonist drugs) treatment group, (5) female gender, and (6) a more severe Unified Parkinson's Disease Rating Scale (UPDRS) Part II. There is clear medical benefit, medically verified neuroprotective effects, and no known toxicity of L-dopa administered either at early stages or at late stages of Parkinsonism. However, there can also be side effects from L-dopa treatment either in combination with or without dopamine agonists: these side effects may include gastrointestinal disturbances, cognitive problems, and sedation. The more recently approved combination therapies of L-dopa with the newer dopamine agonist drugs (also known as dopaminergic substances) still cause dyskinesia in late-stage Parkinson's disease, where this problem persists to the modern day, in the state of the art; a study by Shiraishi (2019) is one such example.
The severe economic impact to families and society from insufficiently comprehensive state-of-the-art neural disease treatments for conditions such as Parkinson's disease remains a burden that society can ill afford. Moreover, the advent of COVID-19 and mutated novel coronavirus has led to a rise in the incidence of Parkinsonism in many affected individuals.
What is therefore needed is a novel therapeutic strategy or unique material used to confer improved cellular neuron protection and significantly prevent, mitigate, or reverse toxic pathology arising from synaptic and neurological dysfunction before irreversible damage progresses. Desirably, such a treatment should prevent or avoid dyskinesia by including a means to remove sources of oxidation and free radical generation, to include a very localized and very targeted remediation of reactive oxygen species. It is believed the present invention provides the first broadly effective discovery of such a composition, having an intelligent biological and electrochemical design to confer multiple therapeutic and prophylactic functions that are highly targeted neural synaptic structures, especially those in the substantia nigra of the brain. This novel composition will change our perspective on applications to boost resistance and generate recovery to the effects of Parkinson's and other motor neuron disease. The use of traditional carrier formulations will enable appropriate methods of administration for this novel composition.
This invention is a molecular cluster of nanoparticles composed with fullerene levodopa gamma amino butyric acid or its metabolized form as fullerene dopamine gamma amino butyric acid. The use of dopamine (DOPA) as a starting material is interchangeable with, and functionally equivalent to, the use of levodopa in the present invention and is hereby explicitly specified. The present invention is an inert mineral particle bonded with two types of neurotransmitters, where the gamma amino butyric acid (GABA) neurotransmitter functional group acts as a reducing agent with the tremendous advantage being that it behaves as an antioxidant to treat and proactively reduce the oxidative conditions leading to neurological disease in neural synaptic structures associated with Parkinson's Disease, Lewy Body Disease, and Inflammatory Bowel Syndrome. Both GABA and the L-Dopa (or DOPA) functional groups or their metabolites confer neuroprotective properties. This composition is also useful to treat amyotrophic lateral sclerosis (ALS), and other neuron and motor neuron diseases or damages. The nanoparticle molecular structure possesses charge storage properties targeted to break plaque forming regions using a salt-bridge disruption technology. The composition promotes free radical scavenging and targeted delivery to brain neurons in a synergistically enabled manner that is enabled by each functional group. The antioxidant properties of the functional groups are deliberately carried to the most oxidatively stressed region at neural structures, being the post synaptic bouton, while also providing a storage reservoir of reducing hydrogen protons on the C60 and the amine functionality of GABA to confer a localized chemical reducing condition.
In a key functional aspect, C60-GABA-L-Dopa and its metabolites to C60-GABA-DOPA provide an artificial pathway to supplement and accelerate the trafficking of cations for proton exchange to prevent or remove salt accumulation among oligomeric fibrils. This function acts to disassemble the oligomeric plaques formed by salt cations by extracting these cations, so that they may not serve as salt bridges. This aspect of the invention depends on the use of the zwitterionic properties of the nanoparticle functional groups. C60 is normally considered anionic when it collects as many as six negative charges. The association of C60 with zwitterionic functional groups has the additional properties of being an organic salt, in which both hydrogen bonding as well as aromatic pi to cationic pi bonding contributes to the stability of these structures and defines how this collective ensemble serves to traffic both protons and physiological cations such as potassium and sodium.
In another aspect, the C60-GABA-DOPA composition protects and enhances the membrane polarization of mitochondria by being able to penetrate them and protect them from oxidative stress. This allows protected mitochondria to significantly enable their normal ATPase function and undisrupted ability to generate reducing protons, where such hydrogen protons are then able to achieve reducing REDOX conditions at the neural post-synaptic terminal.
In a related aspect, the composition of this invention accrues and transports hydrogen protons to regions removed from the mitochondria where protons are required to exchange for physiological cations such as potassium, and sodium. This aspect can supplement endogenous substances fulfilling the same role.
In a related aspect, the free radical protective effect of the C60-GABA-DOPA on mitochondria ensures the uninterrupted mitochondrial provision of chemically reductive protons. In a cascade effect, the produced protons act directly on dopamine molecules to enable them to maintain healthy individual alpha-synuclein fibrils in neurons. The functional individual alpha-synuclein fibrils then bond with the inner (cytosolic) leaflets of the presynaptic and post-synaptic membrane leaflets to stabilize the functional release and reacquisition of synaptic vesicles on neurostimulation.
In a key aspect, the technological hurdle of supplying exogenously produced GABA neurotransmitter to the brain is provided by using a buckminsterfullerene (C60) carrier to enable crossing of the blood brain barrier and allow GAB A's well known and outstanding medical benefits, including reducing blood pressure and enhancing long-term memory, to be directly promoted to each brain region and all brain tissues.
In a related aspect, the transport of GABA into the brain by C60 allows it to be protected by the C60 functional group so that this form of GABA is unable to be easily broken down by neural enzymes, especially those released by astrocytes. This enhanced stability promotes the circulation of GABA with an extended lifetime or residence, in which it acts as both an antioxidant and as a critically important neurotransmitter.
In another aspect, the provision of the GABA functional group on the C60-GABA-DOPA is to substitute for a lack of endogenously produced glutathione (GSH) antioxidant in mitochondria. This replacement is neuroprotective to the mitochondria and acts to enable the ability of the mitochondria to return to a state of homeostasis, where it can now recycle the nanoparticles as modified exogenous neurotransmitters for release. The endogenously produced GABA may then bond with the lipids of the cellular membranes, including lipids at the outer (intracellular) presynaptic membrane leaflets. The promoted presence of endogenously produced GABA acts in like manner to missing glutathione, as a reducing agent to prevent the accumulation of free radicals and oxidative damage to membrane lipids. This protection thereby prevents alpha-synuclein from otherwise forming toxic plaques by cross-linking reactions.
In another aspect, the presence of C60-GABA-DOPA is to penetrate those locations in the neural structures already biochemically attractive to dopamine. The dopamine functionality of the introduced C60-GABA-DOPA is otherwise identical to and complementary with that of native or endogenous dopamine neurotransmitter. The advantages of this targeted delivery system are the highly localized delivery of GABA functionality as well as that of the fullerene groups to provide free radical quenching and powerful antioxidant functions to the lipid surfaces to those oxidative locations where dopamine is required for proper neurotransmission, but in which GABA normally does not migrate, and in which C60 is never found except when externally provided.
The result of these combined functions is to allow time for the proper re-integration of dysfunctional or senescent neural cells by introducing an enhanced REDOX reversibility, and to directly inactivate reactive oxygen species (ROS) in mitochondria and at the surface membranes of cellular organelles to re-establish functional cellular homeostasis.
In a related aspect, the function of the antioxidant fullerene GABA dopamine (C60-GABA-DOPA) is to correctively interact with alpha-synuclein oligomers arising from the otherwise pathological interaction with ordinary dopamine under dysregulated and oxidizing conditions. Thus, C60-GABA-DOPA functions as a dopamine mimetic, being functionally identical to dopamine, and taking part in the same biochemical reactions as dopamine yet providing localized therapeutic reducing conditions critical to regulating neural cell function and restoring healthy neurotransmitter signaling at the synapse.
In yet another related aspect, the function of the antioxidant fullerene GABA dopamine (C60-GABA-DOPA) is to correctively detoxify and depolymerize oligomeric alpha-synuclein located in the vagus nerve and in and among the glia and neurons that control and regulate the digestive tract, thereby correcting ulcerative colitis, inflammatory bowel disease, and crone's disease types of pathologies.
In yet another aspect, C60-GABA-DOPA disrupts sodium ion salt bridges between plaque fibrils to return individual strands of alpha-synuclein fibrils to their proper conformation and neurological function. Largely, it is the presence of the core fullerene molecule being tethered to a dopamine functional group that helps to disassemble detrimental salt bridges between proteins. The high negative charge density acquisition of the fullerene group enables the abstraction and sequestering of sodium cations onto itself and away from the plaque proteins.
In another aspect, the C60-GABA-DOPA provides free radical quenching and antioxidant effects together with free radical recombination via the combined activity of both the GABA functional group and the fullerene C60 group, thereby ensuring a reducing rather than oxidizing role in the presence of the metabolized dopamine functional group in this composition, to deter the formation of alpha-synuclein plaques, and to substantially avoid oxidized dopamine release of hydrogen peroxide to inflict damage on neural tissues.
In another aspect, the C60-GABA-DOPA composition is formulated to allow it to become sequestered into the pores of food grade Transcarpathian zeolite (clinoptilolite) for the purpose of timed-release delivery of the orally administered composition to the digestive tract.
In another aspect, the C60-GABA-DOPA composition is administered in the form of a nano-aerosol for the purpose of immediate aspirated delivery to the lungs, thereby providing more direct access to the blood system for rapid release of the administered inhalant composition to the brain and bypassing the digestive system as well as any oxidative damage incurred by the digestive tract fluids to the composition.
The hypothesis for the type of composition here believed to provide maximum therapeutic benefit to the function of the synapse, is one in which at least one neurotransmitter is selected from those of the pre-synaptic terminal, and the other neurotransmitter is selected from the post synaptic terminal. This considers the ideal C60-multiple neurotransmitter design viewpoint to remediate one synaptic terminal that exclusively favors oxidation conditions while the other synaptic terminal favors reducing conditions. This analogy is much like the cathode and anode electrochemistry of a battery design. Thus, to attempt amelioration of oxidative and reductive biological stress at these locations, the design intent must provide some measure of the opposite REDOX condition to the electrically stressed synaptic regions, thereby recovering molecular structures and recharging the over-charged synaptic system much in the way that a depleted battery can become recharged.
These and other advantages of the present invention will be further understood and appreciated by those skilled in the art by reference to the following written specification, claims, and appended drawings.
Some embodiments are described in detail with reference to the related drawings. Additional embodiments, features, and/or advantages will become apparent from the ensuing description or may be learned by practicing the invention. In the illustrations, which are not drawn to scale, like numerals refer to like features throughout the description. The following description is not to be taken in a limiting sense but is made merely for describing the general principles of the invention.
Preferred embodiments of the invention will now be described, by way of example, with reference to the accompanying drawings, in which:
Some embodiments are described in detail with reference to the related drawings. Additional embodiments, features, and/or advantages will become apparent from the ensuing description or may be learned by practicing the invention. In the illustrations, which are not drawn to scale, like numerals refer to like features throughout the description. The following description is not to be taken in a limiting sense but is made merely for describing the general principles of the invention.
The following detailed description, taken in conjunction with the accompanying drawings, is merely exemplary in nature and is not intended to limit the described embodiments or the application and uses of the described embodiments. Any implementation described herein as “exemplary” or “illustrative” is not necessarily to be construed as preferred or advantageous over other implementations.
Furthermore, there is no intention to be bound by any expressed or implied theory presented in the preceding technical field, background, brief summary or the following detailed description. It is also understood that the specific devices, systems, methods, and processes illustrated in the attached drawings, and described in the following specification, are simply exemplary embodiments of the inventive concepts defined in the appended claims that there may be variations to the drawings, steps, methods, or processes, depicted therein without departing from the spirit of the invention. All these variations are within the scope of the present invention. Hence, specific structural and functional details disclosed in relation to the exemplary embodiments described herein are not to be interpreted as limiting, but merely as a representative basis for teaching one skilled in the art to variously employ the present embodiments in virtually any appropriate form, and it will be apparent to those skilled in the art that the present invention may be practiced without these specific details.
Various terms used in the following detailed description are provided and included for giving a perspective understanding of the function, operation, and use of the present invention, and such terms are not intended to limit the embodiments, scope, claims, or use of the present invention.
Pi-carbonyl bonded functional groups of GABA 571, 573 represented by R1, R2 have formula C4H9NO2, where each of these is a zwitterion at physiological and neutral pH, meaning that the proton from the carboxylic acid group can leave and become associated by hydrogen bonding to the amine nitrogen functional group at the opposing distal end of this structure as is represented by GABA 570. GABA 570 reacts with a multiplicity of substituted C60 510, 540 having at least one pi-bonded dopamine functional group 560, 590 or at least one levodopa functional group 530, 550 to form the derivative C60-GABA-L-dopa provided with a multiplicity of GABA functional groups. As both GABA and L-dopa are zwitterions, and as C60 is normally considered anionic when it collects as many as six negative charges, the association of C60 with these zwitterions has the properties of being an organic salt, in which both hydrogen bonding as well as aromatic pi bonding contribute to the stability of these structures. Composition variations may be tuned by the number but not the type of functional groups, depending on penetrating and trafficking function, and may be from at least one GABA and at least one L-dopa to about 9 GABA and about 6 L-Dopa, in which C60 bonded with 2 DOPA and 3 GABA functional groups presents adequate and sufficient medical improvement in human Parkinson's disease. The dual neurotransmitter functionality of GABA and DOPA adduct with C60 is the novel neurotransmitter structure of C60-GABA-DOPA. It is to be understood that the fully decarboxylated metabolite on reaction completion in which C60-GABA-DOPA resides in the brain is the final metabolized form of this composition which performs therapeutic functions, according to the teachings of the present invention.
The introduction of clusters containing C60-GABA-DOPA 62, 63 into and among alpha-synuclein plaques 62 allows the quenching of free radicals and provides anti-oxidant functionality. Clusters containing C60-GABA-DOPA 62, 63 also store and then release hydrogen protons 66 carried at the amine nitrogen of dopamine or GABA functional groups, wherein up to about five additional hydrogen protons 66 may be carried by the fullerene C60 functional group. Fullerenes are also known for their ability to store as many as six negative charges, whereby the high negative charge concentration in the clusters of C60-GABA-DOPA 62, 63 can extract sodium cations 64 from plaque 62, thereby freely releasing individual alpha-synuclein fibrils 61 from the collective plaque tangle 62. The combination of free-radical quenching, anti-oxidant function, cationic extraction, and free proton release enables the proper function of the dopamine neurotransmitter. The targeting of reductive GABA functional groups from C60-GABA-DOPA to those oxidative locations at the post-synaptic terminal where GABA is needed to counteract the oxidative stress, is accomplished by the chemical affinity of the dopamine ligands within the C60-GABA-DOPA clusters 62, 63. The provision of C60 fullerene as a multifunctional center for these chemistries, in addition to the role of C60 as a hydrogen storage functional group, help to create local reducing conditions amenable to prophylactic neural protection from oxidative stress induced degradation prevention.
In the cellular lysosomes and other cellular vesicles, hydrogen protons 66 are exchanged with sodium 64, potassium 65, and other cations by various endogenous early endosome sodium-hydrogen exchangers such as NHE6. Medical evidence of genetic defects in the proteins used to traffic these cations are associated with the oligomeric agglomeration of plaques such as found in Alzheimer's Disease, some forms of autism, and Christianson syndrome. Alpha synuclein is yet another oligomer that has confirmed salt bridges. Alpha-synuclein needs to be present as individual fibrils to transport cations to biological membranes; a multiplicity of salt bridge hydrogen bonds are represented by the dotted lines 67 to bind the oligomer fibrils together so that they may no longer perform their cation shuttling function. C60-GABA-DOPA functions to artificially accelerate the trafficking of cations for proton exchange using a prosthetic pathway that prevents salt accumulation among the oligomeric fibrils, disassembles the oligomeric plaques formed by salt cations, and extracts the salt cations 64, 65 from alpha synuclein so that cations may not serve as salt bridges. The clusters of C60-GABA-DOPA 62, 63 constitute a prosthetic dual neurotransmitter having properties of both GABA and DOPA to enable this neural disease treatment according to the teachings of the present invention.
Filopodia 720 are slender cytoplasmic neural projections that extend beyond a first neuron 710 and may have at least one synaptic junction 760 with a second neuron illustrated as a partial section of another filopodium extension 750. At least one metabolized C60-GABA-DOPA cluster 768 has been reduced in size to about less than 35 nanometers as part of the metabolic process, which enables it to enter the synaptic cleft between pre-synaptic vesicle 764 and post synaptic terminal 762. Cluster 768 provides multifunctional roles to stabilize the membrane lipid interaction at the synaptic junction 760 where neurotransmitter 766 accumulates within the presynaptic terminal as neural bouton 764 for release into the synaptic gap 767 to be received by neural receptors at the proximal neuron providing the post synaptic terminal 762. Vesicles such as 764 may detach and travel with neurotransmitter 767 while carrying charged cations such as Na+ and Ca+2, wherein independent alpha-synuclein fibrils are critical to maintain the multiplicity of cations as adducts. The redox chemistry homeostasis provided by C60-GABA-DOPA clusters 746, 768 destabilizes plaques by the prevention of the free-radical and oxidative kinetics of alpha-synuclein aggregation, and by extracting cations from between alpha-synuclein fibrils, thereby halting or reversing the formation of oligomeric proteins aggregates and their associated toxicity, according to the teachings of the present invention.
Molecules 888 of the present invention may be injected into the blood using a standard physiological saline solution of from about 0.1 mg/Kg to about 5 mg/Kg, consumed as an oral dosage, or inhaled as a nano-aerosol through the lungs to enter the blood stream directly. The presence of negative electrostatic pi-anionic charges among molecules 888 serves to neutralize the electrostatic cation-pi charges among a multiplicity of toxic oligomeric plaques and prions or prion-like particles 840 to disassemble these agglomerates, whereby the healing process among the affected cells can immediately begin to close the gap among the barrier cells 880 at a multiplicity of gaps or holes as indicated by the large upward facing black arrow to once again establish the healthy condition of contiguous tight binding barrier junctions, in accordance with the teachings of the present invention.
Some of the nano-aerosolized composition is exhaled and shown as particulate clusters 121, 122, 123 within exhaled smokey puffs 124 and 125 emitted on exhalation as indicated by the direction of thin line arrows radiating away from the nose of the subject 127. Delivery of the C60-GABA-L-dopa nano-aerosol composition from dispenser 128 provides antioxidant properties to the mucus airway tissues wherein destruction of free radicals and oxidants associated with motor neuron disease and Parkinson's disease are part of the treatment and alpha-synuclein plaque mitigation is provided using this method. Systems that may be used for the method of dispersion of the C60-GABA-L-dopa represented by dispenser 128, include, without limitation, any of the electronic cigarette devices produced internationally and listed in Appendix 4.1, “Major E-cigarette Manufacturers” of the “2016 Surgeon General's Report: E-Cigarette Use Among Youth and Young Adults” published by the Center for Disease Control and Prevention (CDC), Office of Smoking and Health (OSH) freely available at the CDC.GOV website, and/or any combination of piezoelectric, resistively heated, or inductively heated vaporized fluid delivery methods that can be utilized to deliver the composition of the present invention, especially when approved as a medical drug delivery device. Each embodied variation of such methods without limit are intended to aspirate aerosols as the method of therapeutic substance delivery of the composition of the present invention directed into the nasal cavities, mouth, tracheal breathing orifice, or intubated trachea of a patient. The supply direction of nebulized feed of C60-GABA-L-dopa on inhalation and exhalation are delivered into the airways and lungs of the intended patient by the flow of supplied air as indicated by the direction of upward and downward facing large white arrows 126, when used according to the teachings of the present invention.
The numeric scale ranging from 10 to 90 represents percentage transmittance and has units of percentage (%). The FTIR absorbance peak at 3359 cm-1 is attributed to the amine nitrogen-hydrogen vibration (N—H). At 3200 cm-1 appears an oxygen-hydrogen (O—H) stretching vibration, and at 3046 cm-1 is an aromatic hydrogen stretching vibration. The primary amine functional group is indicated by the two (N—H) bending absorbance vibration bands at 1653 cm-1 and at 1567 cm-1. The peaks between 1064 cm-1 and 1200 cm-1 are due to (C—N) stretching vibrations. The sharp and intense peak at 817 cm-1 indicates the N—H bending vibration. There is evidence of a band at about 1500 cm-1 that can be attributed to the C═C bond in the benzene ring structure. Comparison of the illustrated experimental FTIR data for levodopa 1200 indicates similarity to the FTIR absorbances reported for levodopa that are available from the scientific literature, and may be used for confirmation of the raw material composition according to the teachings of the present invention.
The first broad cluster of peaks present at 1445 m/z is consistent with 3 GABA functional groups and two L-dopa functional groups on one C60 group. It is to be understood that adding more functional groups at the time of sample synthesis will change the average mass of the clustered peak grouping but will not fundamentally change the design of the composition or the identity of the pendant groups. The lack of significant dimeric, trimeric, or tetrameric molecular ion fragments indicates that for this number and composition of pendant groups, there is no significant molecular network structure for this sample of C60-GABA-L-dopa. The overall illustrated mass spectral fingerprint of molecular ion fragments 1900 sufficiently characterizes one embodiment of the C60-GABA-L-dopa molecular system according to the teachings and composition of the present invention.
As variations, combinations and modifications may be made in the construction and methods herein described and illustrated without departing from the scope of the invention, it is intended that all matter contained in the foregoing description or shown in the accompanying drawings shall be interpreted as illustrative rather than limiting. Thus, the breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments but defined in accordance with the foregoing claims appended hereto and their equivalents.
This application is a continuation-in-part of international application PCT/US21/63977 filed Dec. 17, 2021 which claims the benefit of and priority to international application PCT/US21/62908 filed Dec. 10, 2021; both international applications claim the benefit and priority of U.S. provisional patent application 63/154,899 filed on Mar. 1, 2021 and entitled “MOTOR NEURON BOOSTING COMPOSITION AND METHODS.” All three of the aforementioned applications are incorporated by reference herein in their entireties.
| Number | Date | Country | |
|---|---|---|---|
| 63154899 | Mar 2021 | US | |
| 63154899 | Mar 2021 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/US2021/062908 | Dec 2021 | US |
| Child | PCT/US2021/063977 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/US2021/063977 | Dec 2021 | US |
| Child | 17581465 | US |
