WO2020118282A1 | 2020-06-11 |
US20040053850A1 | 2004-03-18 | |||
US20200323817A1 | 2020-10-15 | |||
US20220133687A1 | 2022-05-05 |
WHAT IS CLAIMED IS: 1. A method for treating multiple sclerosis in a subject in which demyelination of nerve cells has occurred, the method comprising administering to said subject a pharmaceutically effective amount of a PKC activator to result in remyelination of the nerve cells in said subject. 2. The method of claim 1, wherein the multiple sclerosis is advanced multiple sclerosis. 3. The method according to any one of claims 1-2, wherein the method results in regeneration of lost synaptic connections in the brain of the subject. 4. The method according to any one of claims 1-3, wherein the PKC activator is a macrocyclic lactone compound. 5. The method of claim 4, wherein the macrocyclic lactone compound is a bryostatin compound. 6. The method of claim 5, wherein the bryostatin compound is bryostatin-1. 7. The method of claim 4, wherein the macrocyclic lactone compound is a bryolog compound. 8. The method of claim 7, wherein the bryolog compound has any of the following structures: , wherein R is selected from t-butyl, phenyl, and (CH2)3-p- Br-phenyl. 9. The method according to any one of claims 1-3, wherein the PKC activator is a polyunsaturated fatty acid, ester thereof, cyclopropanated derivative thereof, epoxidized derivative thereof, or pharmaceutically acceptable salt thereof. 10. The method according to any one of claims 1-3, wherein the PKC activator is a cyclopropanated polyunsaturated fatty acid ester having the following structure: wherein R is an alkyl group. 11. The method according to any one of claims 1-3, wherein the PKC activator is a growth factor or growth factor activating compound that functions as a PKC activator. 12. The method of claim 11, wherein the growth factor is selected from the group consisting of BDNF, HGF, NGF, and IGF. 13. The method according to any one of claims 1-12, wherein the PKC activator is administered intravenously. 14. The method according to any one of claims 1-12, wherein the PKC activator is administered as an oral dosage form. 16. The method according to any one of claims 1-14, wherein the PKC activator is administered in an amount of 10-50 μg/m2 weekly for at least 3 weeks. 17. The method according to any one of claims 1-14, wherein the PKC activator is administered in an amount of 20-50 μg/m2 weekly for at least 1 week. 18. The method according to any one of claims 1-14, wherein the PKC activator is administered in an amount of 20-50 μg/m2 weekly for at least 3 weeks. 19. The method according to any one of claims 1-14, wherein the PKC activator is administered in an amount of 20-40 μg/m2 weekly for at least 1 week. 20. The method according to any one of claims 1-14, wherein the PKC activator is administered in an amount of 20-40 μg/m2 weekly for at least 3 weeks. 21. The method according to any one of claims 1-14, wherein the PKC activator is administered in an amount of 30-50 μg/m2 weekly for at least 1 week. 22. The method according to any one of claims 1-14, wherein the PKC activator is administered in an amount of 30-50 μg/m2 weekly for at least 3 weeks. 23. The method according to any one of claims 1-14, wherein the PKC activator is administered in an amount of 25-40 μg/m2 weekly for at least 1 week. 24. The method according to any one of claims 1-14, wherein the PKC activator is administered in an amount of 25-40 μg/m2 weekly for at least 3 weeks. 25. The method according to any one of claims 1-14, wherein the PKC activator is administered at an initial loading dose of about 15 micrograms per week for two consecutive weeks followed by about 12 micrograms on alternate weeks for a least four weeks. 26. The method according to any one of claims 1-14, wherein the PKC activator is administered at an initial loading dose of about 24 micrograms per week for two consecutive weeks followed by about 20 micrograms on alternate weeks for a least four weeks. 27. The method according to any one of claims 1-14, wherein the PKC activator is administered at an initial loading dose of about 48 micrograms per week for two consecutive weeks followed by about 40 micrograms on alternate weeks for a least four weeks. 28. The method according to any one of claims 1-27, wherein the subject is not administered an NMDA receptor antagonist. 29. A method for reducing or preventing neuroinflammation in a subject having early multiple sclerosis or precursor symptoms to early MS, the method comprising administering to said subject a pharmaceutically effective amount of a PKC activator to result in reduction or prevention of neuroinflammation in said subject. 30. The method of claim 29, wherein the PKC activator is a macrocyclic lactone compound. 31. The method of claim 30, wherein the macrocyclic lactone compound is a bryostatin compound. 32. The method of claim 31, wherein the bryostatin compound is bryostatin-1. 33. The method of claim 30, wherein the macrocyclic lactone compound is a bryolog compound. 34. The method of claim 33, wherein the bryolog compound has any of the following structures: , wherein R is selected from t-butyl, phenyl, and (CH2)3-p- Br-phenyl. 35. The method of claim 29, wherein the PKC activator is a polyunsaturated fatty acid, ester thereof, cyclopropanated derivative thereof, epoxidized derivative thereof, or pharmaceutically acceptable salt thereof. 36. The method of claim 29, wherein the PKC activator is a cyclopropanated polyunsaturated fatty acid ester having the following structure: wherein R is an alkyl group. 37. The method of claim 29, wherein the PKC activator is a growth factor or growth factor activating compound that functions as a PKC activator. 38. The method of claim 37, wherein the growth factor is selected from the group consisting of BDNF, HGF, NGF, and IGF. 39. The method according to any one of claims 29-38, wherein the subject is not administered an NMDA receptor antagonist. |
[0043] A third class of suitable bryostatin analogs are the A-ring bryologs. These bryologs generally have slightly lower affinity for PKC than Bryostatin-1 (6.5 nM, 2.3 nM, and 1.9 nM for bryologs 3, 4, and 5, respectively) and a lower molecular weight. A-ring substituents are important for non-tumorigenesis. [0044] Bryostatin analogs are described, for example, in U.S. Patent Nos.6,624,189 and 7,256,286. Methods using macrocyclic lactones to improve cognitive ability are also described in U.S. Patent No.6,825,229 B2. [0045] In some embodiments, a bryostatin (e.g., bryostatin-1) or bryolog is administered to a subject having early MS or at risk for MS or having precursor symptoms indicative of the onset of early MS, and the bryostatin or bryolog is efficacious in reducing initial inflammation (particularly neuroinflammation) that occurs in MS, particularly early MS. The bryostatin or bryolog may also be efficacious in remyelinating axons that have undergone some level of demyelination. In some embodiments, the bryostatin or bryolog is administered in the absence of an NMDA receptor antagonist. [0046] The PKC activator may also include derivatives of diacylglycerols (DAGs). See, e.g., Niedel et al., Proc. Natl. Acad. Sci. (1983), vol.80, pp.36-40; Mori et al., J. Biochem. (1982), vol. 91, pp. 427-431; Kaibuchi et al., J. BioI. Chem. (1983), vol. 258, pp.6701-6704. Activation of PKC by diacylglycerols is transient, because they are rapidly metabolized by diacylglycerol kinase and lipase. Bishop et al. J. BioI. Chem. (1986), vol.261, pp.6993-7000; Chuang et al. Am. J. Physiol. (1993), vol.265, pp. C927-C933; incorporated by reference herein in their entireties. The fatty acid substitution on the diacylglycerol derivatives may determine the strength of activation. Diacylglycerols having an unsaturated fatty acid may be most active. The stereoisomeric configuration is important; fatty acids with a 1,2-sn configuration may be active while 2,3-sn-diacylglycerols and 1,3-diacylglycerols may not bind to PKC. Cis- unsaturated fatty acids may be synergistic with diacylglycerols. In some embodiments, the PKC activator excludes DAG or DAG derivatives. [0047] The PKC activator may also include isoprenoids. Farnesyl thiotriazole, for example, is a synthetic isoprenoid that activates PKC with a K d of 2.5 µM. Farnesyl thiotriazole, for example, is equipotent with dioleoylglycerol, but does not possess hydrolyzable esters of fatty acids. Gilbert et al., Biochemistry (1995), vol.34, pp. 3916-3920; incorporated by reference herein in its entirety. Farnesyl thiotriazole and related compounds represent a stable, persistent PKC activator. Because of its low molecular weight (305.5 g/mol) and absence of charged groups, farnesyl thiotriazole may readily cross the blood-brain barrier. [0048] Yet other types of PKC activators include octylindolactam V, gnidimacrin, and ingenol. Octylindolactam V is a non-phorbol protein kinase C activator related to teleocidin. The advantages of octylindolactam V (specifically the (-)-enantiomer) may include greater metabolic stability, high potency (EC 50 = 29 nM) and low molecular weight that facilitates transport across the blood brain barrier. Fujiki et al. Adv. Cancer Res. (1987), vol.49 pp.223- 264; Collins et al. Biochem. Biophys. Res. Commun. (1982), vol. 104, pp. 1159-4166, each incorporated by reference herein in its entirety. (7-octylindolactam V) [0049] Gnidimacrin is a daphnane-type diterpene that displays potent antitumor activity at concentrations of 0.1 nM - 1 nM against murine leukemias and solid tumors. It may act as a PKC activator at a concentration of 0.3 nM in K562 cells, and regulate cell cycle progression at the G1/S phase through the suppression of Cdc25A and subsequent inhibition of cyclin- dependent kinase 2 (Cdk2) (100% inhibition achieved at 5 ng/ml). Gnidimacrin is a heterocyclic natural product similar to Bryostatin-1, but somewhat smaller (MW = 774.9 g/mol). [0050] Iripallidal is a bicyclic triterpenoid isolated from Iris pallida. Iripallidal displays anti- proliferative activity in a NCI 60 cell line screen with GI 50 (concentration required to inhibit growth by 50%) values from micromolar to nanomolar range. It binds to PKCα with high affinity (K i = 75.6 nM). It may induce phosphorylation of Erk1/2 in a RasGRP3-dependent manner. Its molecular weight is 486.7 g/mol. Iripallidal is about half the size of Bryostatin-1 and lacks charged groups. [0051] Ingenol is a diterpenoid related to phorbol but less toxic. It is derived from the milkweed plant Euphorbia peplus. Ingenol 3,20-dibenzoate, for example, competes with [3H] phorbol dibutyrate for binding to PKC (K i = 240 nM). Winkler et al., J. Org. Chem. (1995), vol. 60, pp. 1381-1390, incorporated by reference herein. Ingenol-3-angelate exhibits antitumor activity against squamous cell carcinoma and melanoma when used topically. Ogbourne et al. Anticancer Drugs (2007), vol. 18, pp.357-362, incorporated by reference herein. [0052] The PKC activator may also include the class of napthalenesulfonamides, including N- (n-heptyl)-5-chloro-1-naphthalenesulfonamide (SC-10) and N-(6-phenylhexyl)-5-chloro-1- naphthalenesulfonamide. SC-10 may activate PKC in a calcium-dependent manner, using a mechanism similar to that of phosphatidylserine. Ito et al., Biochemistry (1986), vol.25, pp. 4179-4184, incorporated by reference herein. Naphthalenesulfonamides act by a different mechanism than bryostatin and may show a synergistic effect with bryostatin or member of another class of PKC activators. Structurally, naphthalenesulfonamides are similar to the calmodulin (CaM) antagonist W-7, but are reported to have no effect on CaM kinase. [0053] The PKC activator may also include the class of diacylglycerol kinase inhibitors, which indirectly activate PKC. Examples of diacylglycerol kinase inhibitors include, but are not limited to, 6-(2-(4-[(4-fluorophenyl)phenylmethylene]-1-piperidinyl)ethy l)-7-methyl-5H- thiazolo[3,2-a]pyrimidin-5-one (R59022) and [3-[2-[4-(bis-(4- fluorophenyl)methylene]piperidin-1-yl)ethyl]-2,3-dihydro-2-t hioxo-4(1H)-quinazolinone (R59949). [0054] The PKC activator may also be a growth factor, such as fibroblast growth factor 18 (FGF-18) and insulin growth factor, which function through the PKC pathway. FGF-18 expression is up-regulated in learning, and receptors for insulin growth factor have been implicated in learning. Activation of the PKC signaling pathway by these or other growth factors offers an additional potential means of activating PKC. [0055] The PKC activator may or may not also include a hormone or growth factor activator, e.g., a 4-methyl catechol derivative, such as 4-methylcatechol acetic acid (MCBA), which stimulates the synthesis and/or activation of growth factors, such as NGF and BDNF. In turn, NGF and BDNF activate PKC as well as convergent pathways responsible for synaptogenesis and/or neuritic branching. [0056] The PKC activator may also be a polyunsaturated fatty acid (“PUFA”). These compounds are essential components of the nervous system and have numerous health benefits. In general, PUFAs increase membrane fluidity, rapidly oxidize to highly bioactive products, produce a variety of inflammatory and hormonal effects, and are rapidly degraded and metabolized. The inflammatory effects and rapid metabolism is likely the result of their active carbon-carbon double bonds. [0057] In one embodiment, the PUFA is selected from linoleic acid (shown below). [0058] The PKC activator may also be a PUFA or MUFA derivative. In particular embodiments, the PUFA or MUFA derivative is a cyclopropanated derivative. Certain cyclopropanated PUFAs, such as DCPLA (i.e., linoleic acid with cyclopropane at both double bonds), may be able to selectively activate PKC-ε. See Journal of Biological Chemistry, 2009, 284(50): 34514-34521; see also U.S. Patent Application Publication No.2010/0022645 A1. Like their parent molecules, PUFA derivatives are thought to activate PKC by binding to the PS site. [0059] Cyclopropanated fatty acids exhibit low toxicity and are readily imported into the brain where they exhibit a long half-life (t 1/2 ). Conversion of the double bonds into cyclopropane rings prevents oxidation and metabolism to inflammatory byproducts and creates a more rigid U-shaped 3D structure that may result in greater PKC activation. Moreover, this U-shape may result in greater isoform specificity. For example, cyclopropanated fatty acids may exhibit potent and selective activation of PKC-ε. [0060] The Simmons-Smith cyclopropanation reaction is an efficient way of converting double bonds to cyclopropane groups. This reaction, acting through a carbenoid intermediate, preserves the cis-stereochemistry of the parent molecule. Thus, the PKC-activating properties are increased while metabolism into other molecules, such as bioreactive eicosanoids, thromboxanes, or prostaglandins, is prevented. [0061] A particular class of PKC-activating fatty acids is omega-3 PUFA derivatives. In at least one embodiment, the omega-3 PUFA derivatives are selected from cyclopropanated docosahexaenoic acid, cyclopropanated eicosapentaenoic acid, cyclopropanated rumelenic acid, cyclopropanated parinaric acid, and cyclopropanated linolenic acid (CP3 form shown below). [0062] Another class of PKC-activating fatty acids is omega-6 PUFA derivatives. In at least one embodiment, the omega-6 PUFA derivatives are selected from cyclopropanated linoleic acid (“DCPLA,” CP2 form shown below), cyclopropanated arachidonic acid, cyclopropanated eicosadienoic acid, cyclopropanated dihomo-gamma-linolenic acid, cyclopropanated docosadienoic acid, cyclopropanated adrenic acid, cyclopropanated calendic acid, cyclopropanated docosapentaenoic acid, cyclopropanated jacaric acid, cyclopropanated pinolenic acid, cyclopropanated podocarpic acid, cyclopropanated tetracosatetraenoic acid, and cyclopropanated tetracosapentaenoic acid. [0063] Vernolic acid is a naturally occurring compound. However, it is an epoxyl derivative of linoleic acid and therefore, as used herein, is considered an omega-6 PUFA derivative. In addition to vernolic acid, cyclopropanated vernolic acid (shown below) is an omega-6 PUFA derivative. [0064] Another class of PKC-activating fatty acids is the class of omega-9 PUFA derivatives. In at least one embodiment, the omega-9 PUFA derivatives are selected from cyclopropanated eicosenoic acid, cyclopropanated mead acid, cyclopropanated erucic acid, and cyclopropanated nervonic acid. [0065] Yet another class of PKC-activating fatty acids is the class of monounsaturated fatty acid (“MUFA”) derivatives. In at least one embodiment, the MUFA derivatives are selected from cyclopropanated oleic acid (shown below), [0066] and cyclopropanated elaidic acid (shown below). [0067] PKC-activating MUFA derivatives include epoxylated compounds such as trans-9,10- epoxystearic acid (shown below). [0068] Another class of PKC-activating fatty acids is the class of omega-5 and omega-7 PUFA derivatives. In at least one embodiment, the omega-5 and omega-7 PUFA derivatives are selected from cyclopropanated rumenic acid, cyclopropanated alpha-elostearic acid, cyclopropanated catalpic acid, and cyclopropanated punicic acid. [0069] Another class of PKC activators is the class of fatty acid alcohols and derivatives thereof, such as cyclopropanated PUFA and MUFA fatty alcohols. It is thought that these alcohols activate PKC by binding to the PS site. These alcohols can be derived from different classes of fatty acids. [0070] In at least one embodiment, the PKC-activating fatty alcohols are derived from omega-3 PUFAs, omega-6 PUFAs, omega-9 PUFAs, and MUFAs, especially the fatty acids noted above. In at least one embodiment, the fatty alcohol is selected from cyclopropanated linolenyl alcohol (CP3 form shown above), cyclopropanated linoleyl alcohol (CP2 form shown above), cyclopropanated elaidic alcohol (shown above), cyclopropanated DCPLA alcohol, and cyclopropanated oleyl alcohol. [0071] Another class of PKC activators includes fatty acid esters and derivatives thereof, such as cyclopropanated PUFA and MUFA fatty esters. In at least one embodiment, the cyclopropanated fatty esters are derived from omega-3 PUFAs, omega-6 PUFAs, omega-9 PUFAs, MUFAs, omega-5 PUFAs, and omega-7 PUFAs. These compounds are thought to activate PKC through binding on the PS site. One advantage of such esters is that they are generally considered to be more stable that their free acid counterparts. [0072] In one embodiment, the PKC-activating fatty acid esters derived from omega-3 PUFAs are selected from cyclopropanated eicosapentaenoic acid methyl ester (CP5 form shown below) [0073] and cyclopropanated linolenic acid methyl ester (CP3 form shown below). [0074] In another embodiment, the omega-3 PUFA esters are selected from esters of DHA- CP6 and aliphatic and aromatic alcohols. In at least one embodiment, the ester is cyclopropanated docosahexaenoic acid methyl ester (CP6 form shown below). [0075] In one embodiment, PKC-activating fatty esters derived from omega-6 PUFAs are selected from cyclopropanated arachidonic acid methyl ester (CP4 form shown below), [0076] cyclopropanated vernolic acid methyl ester (CP1 form shown below), and [0077] vernolic acid methyl ester (shown below). [0078] In particular embodiments, the PKC activating compound is an ester derivative of DCPLA (CP6-linoleic acid). In one embodiment, the ester of DCPLA is an alkyl ester. The alkyl group of the DCPLA alkyl esters may be linear, branched, and/or cyclic. The alkyl groups may be saturated or unsaturated. When the alkyl group is an unsaturated cyclic alkyl group, the cyclic alkyl group may be aromatic. The alkyl group may be selected from, for example, methyl, ethyl, propyl (e.g., isopropyl), and butyl (e.g., tert-butyl) esters. DCPLA in the methyl ester form (“DCPLA-ME”) is shown below. [0079] In another embodiment, the esters of DCPLA are derived from a benzyl alcohol (unsubstituted benzyl alcohol ester shown below). In yet another embodiment, the esters of DCPLA are derived from aromatic alcohols such as phenols used as antioxidants and natural phenols with pro-learning ability. Some specific examples include estradiol, butylated hydroxytoluene, resveratrol, polyhydroxylated aromatic compounds, and curcumin. [0080] Another class of PKC activators includes fatty esters derived from cyclopropanated MUFAs. In an embodiment, the cyclopropanated MUFA ester is selected from cyclopropanated elaidic acid methyl ester (shown below), [0081] and cyclopropanated oleic acid methyl ester (shown below). [0082] Another class of PKC activators includes sulfates and phosphates derived from PUFAs, MUFAs, and their derivatives. In an embodiment, the sulfate is selected from DCPLA sulfate and DHA sulfate (CP6 form shown below). [0083] In one embodiment, the phosphate is selected from DCPLA phosphate and DHA phosphate (CP6 form shown below). [0084] In some embodiments, the PKC activator is selected from macrocyclic lactones, bryologs, diacylglycerols, isoprenoids, octylindolactam, gnidimacrin, ingenol, iripallidal, napthalenesulfonamides, diacylglycerol inhibitors, growth factors, polyunsaturated fatty acids, monounsaturated fatty acids, cyclopropanated polyunsaturated fatty acids, cyclopropanated monounsaturated fatty acids, fatty acids alcohols and derivatives, or fatty acid esters. In some embodiments, any two or more of the above disclosed PKC activators may be administered to the subject in combination. [0085] In some embodiments, the PKC activator (e.g., bryostatin or bryolog) is administered in combination with one or more other substances (i.e., co-drugs, typically, non-PKC activating) known to promote remyelination or reduce neurological inflammation or the known symptoms of MS. Alternatively, the one or more co-drugs may favorably or synergistically augment the efficacy of the PKC activator in remyelinating neural tissue or treating neurological inflammation, particularly in MS. The one or more co-drugs may be administered separately (e.g., same or different days or weeks) but in tandem with the administration of the PKC activator, or the one or more co-drugs may be included within the same pharmaceutical formulation as the PKC activator, thereby being administered to the subject at the same time within the same dosage form. The co-drug may be, for example, an immunomodulating drug (e.g., glatiramer acetate), monoclonal antibody acting as α4 integrin antagonist (e.g., natalizumab), a hormone (e.g., melatonin), antibiotic (e.g., minocycline), steroid or corticosteroid (e.g., corticotrophin, cortisone, methylprednisolone, or clobetasol), cytokine in the interferon family (e.g., interferon beta-1a or interferon beta 1-alpha), statin (e.g., simvastatin), or an antifungal or ERK activity enhancer (e.g., miconazole). [0086] The PKC activators according to the present disclosure may be administered to a patient/subject in need thereof by conventional methods, such as oral, parenteral, transmucosal, intranasal, inhalation, or transdermal administration. Parenteral administration includes intravenous, intra-arteriolar, intramuscular, intradermal, subcutaneous, intraperitoneal, intraventricular, intrathecal, ICV, intracisternal injections or infusions and intracranial administration. A suitable route of administration may be chosen to permit crossing the blood- brain barrier. See e.g., J. Lipid Res. (2001) vol. 42, pp. 678-685, incorporated by reference herein. [0087] The PKC activators can be compounded into a pharmaceutical composition suitable for administration to a subject using general principles of pharmaceutical compounding. In one aspect, the pharmaceutically acceptable formulation comprises a PKC activator and a pharmaceutically acceptable carrier. One or more co-drugs, as described above, may or may not also be included in the formulation. [0088] The formulations of the compositions described herein may be prepared by any suitable method known in the art. In general, such preparatory methods include bringing at least one of the active ingredients into association with a carrier. If necessary or desirable, the resultant product can be shaped or packaged into a desired single- or multi-dose unit. [0089] As discussed herein, carriers include, but are not limited to, one or more of the following: excipients; surface active agents; dispersing agents; inert diluents; granulating and disintegrating agents; binding agents; lubricating agents; sweetening agents; flavoring agents; coloring agents; preservatives; physiologically degradable compositions such as gelatin; aqueous vehicles and solvents; oily vehicles and solvents; suspending agents; dispersing or wetting agents; emulsifying agents, demulcents; buffers; salts; thickening agents; fillers; emulsifying agents; antioxidants; antibiotics; antifungal agents; stabilizing agents; and pharmaceutically acceptable polymeric or hydrophobic materials. Other additional ingredients that may be included in the compositions of the disclosure are generally known in the art and may be described, for example, in Remington's Pharmaceutical Sciences, Genaro, ed., Mack Publishing Co., Easton, Pa., 1985, and Remington's Pharmaceutical Sciences, 20 th Ed., Mack Publishing Co.2000, both incorporated by reference herein. [0090] In at least one embodiment, the carrier is an aqueous or hydrophilic carrier. In a further embodiment, the carrier may be water, saline, or dimethylsulfoxide. In another embodiment, the carrier is a hydrophobic carrier. Exemplary hydrophobic carriers include, for example, inclusion complexes, dispersions (such as micelles, microemulsions, and emulsions), and liposomes. See, e.g., Remington's: The Science and Practice of Pharmacy 20th ed., ed. Gennaro, Lippincott: Philadelphia, PA 2003, incorporated by reference herein. In addition, other compounds may be included either in the hydrophobic carrier or the solution, e.g., to stabilize the formulation. [0091] In some embodiments, the compositions described herein may be formulated into oral dosage forms. For oral administration, the composition may be in the form of a tablet or capsule prepared by conventional means with, for example, carriers such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). The tablets may be coated by methods generally known in the art. [0092] In another embodiment, the compositions herein are formulated into a liquid preparation. Such preparations may be in the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means using pharmaceutically acceptable carriers, such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils); and preservatives (e.g., methyl or propyl p-hydroxybenzoates, or sorbic acid). The preparations may also comprise buffer salts, flavoring, coloring, and sweetening agents as appropriate. In some embodiments, the liquid preparation is specifically designed for oral administration. [0093] In another embodiment of the present disclosure, the compositions herein may be formulated for parenteral administration such as bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules, or in multi- dose containers, with an added preservative. The composition may be in the form of a suspension, solution, dispersion, or emulsion in oily or aqueous vehicles, and may contain a formulary agent, such as a suspending, stabilizing, and/or dispersing agent. [0094] In another embodiment, the compositions herein may be formulated as depot preparations. Such formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. For example, the compositions may be formulated with a suitable polymeric or hydrophobic material (for example, as an emulsion in an acceptable oil) or ion exchange resin, or as a sparingly soluble derivative, for example, as a sparingly soluble salt. [0095] In another embodiment, at least one PKC activator or combination thereof is delivered in a vesicle, such as a micelle, liposome, or an artificial low-density lipoprotein (LDL) particle. See, e.g., U.S. Patent No.7,682,627, the contents of which are herein incorporated by reference. [0096] In some embodiments, at least one PKC activator or combination of PKC activators may be present in the pharmaceutical composition in an amount ranging from about 0.01% to about 100%, from about 0.1% to about 90%, from about 0.1% to about 60%, from about 0.1% to about 30% by weight, or from about 1% to about 10% by weight of the final formulation. In another embodiment, at least one PKC activator or combination of PKC activators may be present in the composition in an amount ranging from about 0.01% to about 100%, from about 0.1% to about 95%, from about 1% to about 90%, from about 5% to about 85%, from about 10% to about 80%, and from about 25% to about 75%. [0097] The present disclosure further relates to kits that may be utilized for administering to a subject a PKC activator according to the present disclosure. The kits may comprise devices for storage and/or administration. For example, the kits may comprise syringe(s), needle(s), needle-less injection device(s), sterile pad(s), swab(s), vial(s), ampoule(s), cartridge(s), bottle(s), and the like. The storage and/or administration devices may be graduated to allow, for example, measuring volumes. In at least one embodiment, the kit comprises at least one PKC activator in a container separate from other components in the system. [0098] The kits may also comprise one or more anesthetics, such as local anesthetics. In at least one embodiment, the anesthetics are in a ready-to-use formulation, for example, an injectable formulation (optionally in one or more pre-loaded syringes), or a formulation that may be applied topically. Topical formulations of anesthetics may be in the form of an anesthetic applied to a pad, swab, towelette, disposable napkin, cloth, patch, bandage, gauze, cotton ball, Q-tip™, ointment, cream, gel, paste, liquid, or any other topically applied formulation. Anesthetics for use with the present disclosure may include, but are not limited to lidocaine, marcaine, cocaine, and xylocaine. [0099] The kits may also contain instructions relating to the use of at least one PKC activator or a combination thereof. In another embodiment, the kit may contain instructions relating to procedures for mixing, diluting, or preparing formulations of at least one PKC activator or a combination thereof. The instructions may also contain directions for properly diluting a formulation of at least one PKC activator or a combination thereof in order to obtain a desired pH or range of pHs and/or a desired specific activity and/or protein concentration after mixing but prior to administration. The instructions may also contain dosing information. The instructions may also contain material directed to methods for selecting subjects for treatment with at least one PKC activator or a combination thereof. [0100] The PKC activator can be formulated, alone in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. Pharmaceutical compositions may further comprise other therapeutically active compounds which are approved for the treatment of neurodegenerative diseases or to reduce the risk of developing a neurodegenerative disorder. [0101] All of the references, patents and printed publications mentioned in the instant disclosure are hereby incorporated by reference in their entirety into this application. [0102] The following examples are provided by way of illustration to further describe certain preferred embodiments of the invention, and are not intended to be limiting of the present disclosure. EXAMPLES [0103] In vitro or in vivo studies may be performed using a PKC activating compound, such as a bryostatin (e.g., bryostatin-1) or bryolog. An experimental autoimmune encephalomyelitis (EAE) mouse model, in particular, may be used for modeling demyelination or neurological inflammation, such as occurs in MS (A. P. Robinson et al., Hand. Clin. Neurol., 122, pp.173- 189, 2014). By known methods, EAE can be first initiated (induced) by immunization with a specific CNS antigen, such as myelin oligodendrocyte glycoprotein (MOG) or other inducer, to induce encephalomyelitis. Some of the mice are then administered the PKC activating compound either before, during, or after induction to determine the efficacy of the compound on initiation or development of EAE. In the case of administering the PKC activating compound before or at the start of MOG immunization, the PKC activating compound may result in prevention of the induction of EAE, which may indicate ability of the PKC activating compound to prevent demyelination, induce remyelination in later MS, or reduce or prevent neuroinflammation in early MS. In the case of administering the PKC activating compound after induction of EAE, the PKC activating compound may result in suppression, halting, or even reversal of EAE development, which may indicate ability of the PKC activating compound to suppress, halt, or even reverse demyelination (i.e., by remyelination) in MS. [0104] Groups of 2-3 mice may be formed and housed in an approved research animal facility. Water may be given ad libitum. A first study involves three groups of mice with animals in each group dosed weekly for 1, 2, 3, or 6 consecutive weeks. Each group has its own control group containing the same number of mice. For example, mice in the first, second and third groups may receive an intravenous (i.v.) injection of 10 µg/m 2 , 15 µg/m 2 , and 25 µg/m 2 dose of a bryostatin, bryolog, or other PKC activating compound, respectively. For each dose, mice in that group may receive a single injection of a bryostatin, bryolog, or other PKC activating compound weekly for a predetermined number of consecutive weeks. Following dosing, mice are generally sacrificed and the blood and brain of each animal may be collected for further analysis. [0105] In some cases, mice are dosed weekly with a bryostatin, bryolog, or other PKC activating compound at about 25 µg/m 2 for three consecutive weeks, followed by cessation of drug administration for three consecutive weeks, and then a second round of dosing at about 25 µg/m 2 for an additional three consecutive weeks (that is, a “3 on/3 off/3 on” dosing regimen). In other embodiments, mice are dosed at about 25 µg/m 2 at a “1 on/1 off” regimen for a total of nine weeks (e.g., one dose of a bryostatin, bryolog, or other PKC activating compound on weeks 1, 3, 5, 7, and 9, with no dosing in weeks 2, 4, 6, and 8). In other embodiments, mice are dosed at about 25 µg/m 2 for another regimen starting with “2 on/1 off” immediately followed by alternating “1 on/1 off” until reaching the ninth total week (i.e., one dose of a bryostatin, bryolog, or other PKC activating compound on weeks 1, 2, 4, 6, 8, with no dosing in weeks 3, 5, 7, and 9). Increasing the duration of the rest intervals (i.e., “off” intervals) to three weeks may significantly reduce PKC downregulation. That is, the “3 on/3 off” dosing regimen may increase brain PKC-ε levels in mice over the other regimens, thus resulting in particularly beneficial results. [0106] Brain BDNF in mice may reach its highest level after three consecutive weekly doses of a bryostatin, bryolog, or other PKC activating compound at about 25 µg/m 2 and remain elevated after three additional consecutive weeks of no dosing, followed by three more consecutive weekly doses at about 25 µg/m 2 . Since BDNF is a peptide that induces synaptogenesis (i.e., the formation of new synapses), a “3 on/3 off” regimen may maximize synaptogenesis and minimize PKC downregulation. [0107] Further evaluation may be performed on a bryostatin, bryolog, or other PKC activating compound crossing the blood-brain-barrier (BBB) and the steady state levels of a bryostatin, bryolog, or other PKC activating compound in the brain and plasma of mice. In some embodiments, a bryostatin, bryolog, or other PKC activating compound administered intravenously crosses the BBB. In that case, the concentration of a bryostatin, bryolog, or other PKC activating compound in mice brain may be less than its concentration in plasma. However, the concentration in brain may be no less than two-fold lower than the plasma concentrations for comparable doses under steady-state conditions. [0108] A weekly dosing regimen of a single injection of a bryostatin, bryolog, or other PKC activating compound at a dose of about 25 µg/m 2 for three consecutive weeks may be less effective at increasing the concentration of a bryostatin, bryolog, or other PKC activating compound in mice brain than a “1 on/1 off” or a “2 on/1 off” administration of the 25 µg/m 2 dose. In contrast, plasma concentrations of a bryostatin, bryolog, or other PKC activating compound may be greater when the drug is administered as a single injection for three consecutive weeks. Blood plasma concentrations of a bryostatin, bryolog, or other PKC activating compound may be less in mice receiving a 25 µg/m 2 dose as a “1 on/1 off” or a “2 on/1 off” administration. Without being bound to a specific theory, it may be hypothesized that the intermittent dosing regimen facilitates the transport of a bryostatin, bryolog, or other PKC activating compound across the BBB. [0109] While there have been shown and described what are at present considered the preferred embodiments of the invention, those skilled in the art may make various changes and modifications which remain within the scope of the invention defined by the appended claims.
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